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RAS
RAS
RAS(14) FTS(15)


RAS is a small farneslyated, GTPase critical for a number of pathways leading to MEK/ERK activation.(1,2) When Ras is activated, it activates other proteins, which ultimately turn on genes involved in cell growth, differentiation, survival, actin cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration.
GEFs, such as Sos and cdc25, facilitate Ras activation. The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity.(2) Activated Ras has binds numerous effectors, such as PI3K, AKT, and MAPK.(2)
Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis.(2, 3) Mutations in Ras genes can lead to the production of permanently activated Ras proteins. Activating mutations of Ras and upstream elements may play a role in more than two thirds of all human cancers.(2) Mutations of RAS genes or overexpression of RAS occurs in high frequency in MDS and AML. Leukemic cells from roughly 10-40% of MDS cases and 15-25% of AML cases have been reported to have RAS mutations.(6) The 3 Ras genes in humans (HRAS, KRAS, and NRAS) are the most common oncogenes in human cancer.(2,4,5) Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras. The tumor suppressor gene NF1 encodes a Ras-GAP - its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumors. Ras oncogenes can be activated by point mutations so that the GTPase reaction can no longer be stimulated by GAP - this increases the half-life of active Ras-GTP mutants.(2) Mutations of RAS genes, or activation of RAS in the absence of mutations, occurs in high frequency in MDS and AML.(6)
Farnesyltransferase's targets include members of the Ras superfamily of small GTP-binding proteins critical to cell cycle progression. Farnesylation causes farnesylated proteins to become membrane-associated due to the hydrophobic nature of the farnesyl group. Most farnesylated proteins are involved in cellular signaling. FTS is also believed to play an important role in development of progeria and various forms of cancers. FTS is one of the three enzymes in the prenyltransferase group. FTS adds a 15-carbon isoprenoid called a farnesyl group to to the -SH of the cysteine near the end of target CaaX motif proteins to form a thioether linkage proteins.
Farnesyltransferase inhibitors (FTIs) represent an effective method to disrupt RAS function by blocking its ability to anchor to the plasma membrane, causing a GDP-locked, inactive state.(6) Targeted disruption of FTase activity leads to the inactivation of RAS function.(6, 7) The farnesyl group on Ras is necessary for movement from the cytoplasm to the plasma membrane and for membrane anchorage; a process that is essential for activation.(8) Of all the targeted inhibitors developed, tipifarnib represents one of the few compounds with some activity as a single agent against AML and MDS. Although the drug is highly selective for FTase, a plethora of activities result from the numerous cellular proteins that require farnesylation for activity. In 2005 FDA did not grant approval for tipifarnib, a request based on Phase II data. Subsequently, a Phase III study did not confirm activity as a single agent for the treatment of older AML patients. JNJ is no longer supporting tipifarnib as a therapeutic for AML because of the negative Phase III trial utilizing tipifarnib as a single agent.(6) Reovirus reproduces well in certain cancer cell lines activated Ras pathway. Reovirus replicates in and eventually kills Ras-activated tumor cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. Type II herpes simplex virus (HSV-2) also targets tumor cells with an activated Ras pathway.(2)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
salirasib KD032 Ono P2: NSCLC trials
siG12D Silenseed P2: pancreatic trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
lonafarnib SCH 66336 Sarasar Merck terminated; P3: NSCLC, MDS, CML; P2: BC, bladder, RCC, urethral, ovarian, HCC, HNN, GBM; P1/2: PC, gastric; P1: squamous, CNS trials
tipifarnib R115777 Topotecan, Zarnestra, Hycamptin JNJ Rejected FDA 2005; P3: pancreatic, AML; P2/3: MDS; P2: NSCLC, CRC, bladder, astrocytoma, brain, CNS, MM, melanoma, GBM, CLL, MCL, BC, thyroid; P1: solid trials
diazepinomicin TLN-4601 ECO-4601 Thallion terminated due to lack of efficacy; P2: GBM; P1: glioma, CRC, lung, BC, ovarian, pancreatic, PC trials
RAS peptide vaccine noncorporate Last trial started in 1999; P2: lung, leukemia, MDS trials
ISIS 2503 Isis terminated; P2: pancreatic, CRC trials
TG01 Targovax Tragara Last new trial started in 2007; P1: NSCLC trials
BMS-214662 BMS Last new trial started in 2001; P1: solid, CML, ALL, AML trials
CP-609,754 Pfizer Last new trial started in 2000; P1: solid trials
L-778,123 noncorporate Last new trial started in 2000; P1: solid, HNN, lymphoma trials
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References

1. Li Na, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993;363(6424):85-8.

2. Ras_subfamily. Available from: http://en.wikipedia.org/wiki/Ras_subfamily.

3. Goodsell DS. The molecular perspective: the ras oncogene. The oncologist. 1999;4(3):263-4.

4. Downward J. Targeting RAS signalling pathways in cancer therapy. Nature Reviews Cancer. 2003;3(1):11-22.

5. Bos JL. Ras oncogenes in human cancer: a review. CANCER RESEARCH. 1989;49(17):4682-9.

6. Epling-Burnette PK, Loughran Jr TP. Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib. Expert opinion on investigational drugs. 2010;19(5):689-98.

7. Agrawal AG, Somani RR. Farnesyltransferase inhibitor as anticancer agent. Mini reviews in medicinal chemistry. 2009;9(6):638-52.

8. de Rooij J, Bos JL. Minimal Ras-binding domain of Raf1 can be used as an activation-specific probe for Ras. Oncogene. 1997;14(5):623-5.

9. Mattison RJ, Ostler KR, Locke FL, Godley LA. Implications of FLT3 mutations in the therapy of acute myeloid leukemia. Reviews on recent clinical trials. 2007;2(2):135-41.

10. Ehmann F, Horn S, Garcia-Palma L, Wegner W, Fiedler W, Giehl K, Mayr GW, Jcker M. Detection of N-RAS and K-RAS in their active GTP-bound form in acute myeloid leukemia without activating RAS mutations. Leukemia & lymphoma. 2006;47(7):1387-91.

11. Rcher C, Dos Santos C, Demur C, Payrastre B. Review mTOR, A New Therapeutic Target in Acute Myeloid Leukemia. Cell Cycle. 2005;4(11):1540-9.

12. Faderl S, Pal A, Bornmann W, Albitar M, Maxwell D, Van Q, Peng Z, Harris D, Liu Z, Hazan-Halevy I. Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells. CANCER RESEARCH. 2009;69(9):3910-7.

13. Dickson DJ, Sham PJ. Angiogenesis in acute and chronic leukemias. Leukemia & lymphoma. 2001;42(5):847-53.

14. Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H. Protein tyrosine phosphatase SHP?2: A proto?oncogene product that promotes Ras activation. Cancer science. 2009;100(10):1786-93.

15. FTS. Available from: http://www.umich.edu/~caflab/ftase.htm.



News
11:00 PM|Egeli, Unal; Tezcan, Gulcin; Cecener, Gulsah; Tunca, Berrin; Demirdogen Sevinc, Elif; Kaya, Ekrem; Ak, Secil; Dundar, Halit Ziya; Sarkut, Pinar; Ugras, Nesrin; Yerci, Omer; Ozen, Yilmaz; Evrensel, Turkkan|Pancreas - Current Issue|Labels: EGFR, FGFR, RAS, pancreatic cancer
imageObjectives: The success of gemcitabine plus radiotherapy is dependent on the mutation status of pancreatic ductal adenocarcinoma (PDAC) tumors in the EGFR and KRAS genes; however, radiotherapy resistance may also be modulated epigenetically by microRNA (miRNA) regulation. In this study, we examined the potential effect of miRNAs on the resistance to radiotherapy in cases without EGFR or KRAS mutation. Methods: The association of EGFR and KRAS mutation status and different expression patterns of 6 selected miRNAs related to the EGFR/KRAS signaling pathway were evaluated in the tumors of 42 patients with PDAC. Results: Reduced miR-216b and miR-217 expression was associated with aggressive tumor characteristics and shortened disease-free survival. In addition, miR-216b expression was reduced 2.7-fold in the cases that did not benefit from therapy, although they did not demonstrate EGFR or KRAS expression (P = 0.0316). A negative correlation between FGFR1 and miR-216b expression (r = −0.355) was found in the tumors of these cases. Conclusions: Further studies and validations are required; in the tumors of patients with PDAC without activating mutations and induced expression of EGFR/KRAS genes, down-regulated miR-216b expression may be associated with a poor response to radiotherapy via deregulation of another signaling pathway related to FGFR1 signaling.
11:00 PM|Farchoukh, Lama; Kuan, Shih-Fan; Dudley, Beth; Brand, Randall; Nikiforova, Marina; Pai, Reetesh K.|The American Journal of Surgical Pathology - Current Issue|Labels: BRAF, RAS, CRC
imageBetween 10% and 15% of colorectal carcinomas demonstrate sporadic DNA mismatch-repair protein deficiency as a result of MLH1 promoter methylation and are thought to arise from sessile serrated adenomas, termed the serrated neoplasia pathway. Although the presence of the BRAF V600E mutation is indicative of a sporadic cancer, up to 30% to 50% of colorectal carcinomas with MLH1 promoter hypermethylation will lack a BRAF mutation. We report the clinicopathologic and molecular features of MLH1-deficient colorectal carcinoma with wild-type BRAF and MLH1 promoter hypermethylation (referred to as MLH1-hypermethylated BRAF wild-type colorectal carcinoma, n=36) in comparison with MLH1-deficient BRAF-mutated colorectal carcinoma (n=113) and Lynch syndrome–associated colorectal carcinoma (n=36). KRAS mutations were identified in 31% of MLH1-hypermethylated BRAF wild-type colorectal carcinomas compared with 0% of MLH1-deficient BRAF-mutated colorectal carcinomas and 37% of Lynch syndrome–associated colorectal carcinomas. When a precursor polyp was identified, MLH1-hypermethylated BRAF wild-type colorectal carcinomas arose from precursor polyps resembling conventional tubular/tubulovillous adenomas in contrast to MLH1-deficient BRAF-mutated colorectal carcinomas, which arose from precursor sessile serrated adenomas (P<0.001). Both MLH1-hypermethylated BRAF wild-type colorectal carcinoma and MLH1-deficient BRAF-mutated colorectal carcinoma had a predilection for the right colon compared with Lynch syndrome–associated colorectal carcinoma (86% vs. 92% vs. 49%, P<0.001). There was no significant difference in mucinous differentiation, tumor-infiltrating lymphocytes, Crohn-like reaction, and medullary differentiation between the 3 tumor groups. Using Kaplan-Meier survival functions, there was no significant difference in disease-specific survival between the 3 patient groups (P>0.05). In conclusion, our results indicate that MLH1-hypermethylated BRAF wild-type colorectal carcinomas can harbor KRAS mutations and arise from precursor polyps resembling conventional tubular/tubulovillous adenomas.
12:52 PM|Oshima, K., Khiabanian, H., da Silva-Almeida, A. C., Tzoneva, G., Abate, F., Ambesi-Impiombato, A., Sanchez-Martin, M., Carpenter, Z., Penson, A., Perez-Garcia, A., Eckert, C., Nicolas, C., Balbin, M., Sulis, M. L., Kato, M., Koh, K., Paganin, M., Basso, G., Gastier-Foster, J. M., Devidas, M., Loh, M. L., Kirschner-Schwabe, R., Palomero, T., Rabadan, R., Ferrando, A. A.|PNAS - RSS feed of Early Edition articles|Labels: RAS, ALL
Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous...
Contributors : Bernard Omolo ; Mingli Yang ; Fang Y Lo ; Michael J Schell ; Sharon Austin ; Kellie Howard ; Anup Madan ; Timothy J Yeatman
Series Type : Expression profiling by high throughput sequencing
Organism : Homo sapiens

Background: The KRAS gene is mutated in about 40% of colorectal cancer (CRC) cases, which has been clinically validated as a predictive mutational marker of intrinsic resistatnce to anti-EGFR inhibitor (EGFRi) therapy. Since nearly 60% of patients with a wild type KRAS fail to respond to EGFRi treatment, there is a need to develop more reliable molecular signatures to better predict response. Here we address the challenge of adapting a gene expression signature predictive of RAS pathway activation, created using fresh frozen (FF) tissues, for use with more widely available formalin fixed paraffin-embedded (FFPE) tissues.
Methods: In this study, we evaluated the translation of an 18-gene RAS pathway signature score from FF to FFPE in 54 CRC cases, using a head-to-head comparison of five technology platforms. FFPE-based technologies included the Affymetrix GeneChip (Affy), NanoString nCounter(NanoS), Illumina whole genome RNASeq (RNA-Acc), Illumina targeted RNASeq(t-RNA), and Illumina stranded Total RNA-rRNA-depletion (rRNA).
Results: Using Affy_FF as the "gold" standard, initial analysis of the 18-gene RAS scores on all 54 samples shows varying pairwise Spearman correlations, with (1) Affy_FFPE(r=0.233, p=0.090); (2) NanoS_FFPE(r=0.608, p<0.0001); (3) RNA-Acc_FFPE(r=0.175, p=0.21); (4) t-RNA_FFPE (r=-0.237, p=0.085); and (5) t-RNA (r=-0.012, p=0.93). These results suggest that only NanoString has successful FF to FFPE translation. The subsequent removal of identified "problematic" samples (n=15) and gene (n=2) further improves the correlations of Affy_FF with three of the five technologies: Affy_FFPE (r=0.672, p<0.0001); NanoS_FFPE (r=0.738, p<0.0001); and RNA-Acc_FFPE (r=0.483, p=0.002).
Conclusions: Of the five technology platforms tested, NanoString technology provides a more faithful translation of the RAS pathway gene expression signature from FF to FFPE than the Affymetrix GeneChip and multiple RNASeq technologies. Moreover, NanoString was the most forgiving technology in the analysis of samples with presumably poor RNA quality. Using this approach, the RAS signature score may now be reasonably applied to FFPE clinical samples.

Contributors : Elena G Seviour ; Vasuda Sehgal ; Dhruva Mishra ; Rajesha Rupaimoole ; Cristian Rodriguez-Aguayo ; Gabriel Lopez-Berestein ; Ju-Seog Lee ; Anil K Sook ; Min P Kim ; Gordon B Mills ; Prahlad T Ram
Series Type : Expression profiling by array
Organism : Homo sapiens

Ras family oncogenes are mutated in approximately 30% of human cancers and cause resistance to multiple treatment modalities. While identifying methods to directly target mutant KRas have been challenging, targeting regulators of KRas may be beneficial. Using a systems approach of integrating a genome-wide miRNA screen with patient data of a phospho-proteomic signature of the KRas downstream pathway, we identified miR-193a-3p as a potent tumor suppressor capable of reversing KRas-related signaling, whereby the 3’UTR of KRas is directly targeted via two miR-193a-3p binding sites. Mechanistic studies revealed that miR-193a-3p inhibited the KRas protein signature, KRas downstream transcriptomic network, proliferation, induced a G1 arrest, and reduced colony formation in 3D cultures through direct targeting of KRas. An ex vivo lung cancer model showed that miR-193a-3p significantly reduced the viability of circulating tumor cells as well as decreased metastasis. In vivo studies revealed that miR-193a-3p significantly reduced tumor growth as well as metastasis of a KRas-mutant lung cancer xenograft model.

Friday, September 16, 2016 4:27 PM|David J. Clark, Yuping Mei, Shisheng Sun, Hui Zhang, Austin J. Yang, Li Mao|Theranostics|Labels: RAS, lung cancer

Protein glycosylation plays a fundamental role in a multitude of biological processes, and the associated aberrant expression of glycoproteins in cancer has made them attractive biomarkers and therapeutic targets. In this study, we examined differentially expressed glycoproteins in cell lines derived from three different states of lung tumorigenesis: an immortalized bronchial epithelial cell (HBE) line, a non-small cell lung cancer (NSCLC) cell line harboring a Kirsten rat sarcoma viral oncogene homolog (KRAS) activation mutation and a NSCLC cell line harboring an epidermal growth factor receptor (EGFR) activation deletion. Using a Triple SILAC proteomic quantification strategy paired with hydrazide chemistry N-linked glycopeptide enrichment, we quantified 118 glycopeptides in the three cell lines derived from 82 glycoproteins. Proteomic profiling revealed 27 glycopeptides overexpressed in both NSCLC cell lines, 6 glycopeptides overexpressed only in the EGFR mutant cells and 19 glycopeptides overexpressed only in the KRAS mutant cells. Further investigation of a panel of NSCLC cell lines found that Cellular repressor of E1A-stimulated genes (CREG1) overexpression was closely correlated with KRAS mutation status in NSCLC cells and could be down-regulated by inhibition of KRAS expression. Our results indicate that CREG1 is a down-stream effector of KRAS in a sub-type of NSCLC cells and a novel candidate biomarker or therapeutic target for KRAS mutant NSCLC.

Friday, September 16, 2016 10:23 AM|Craig D. Logsdon, Weiqin Lu|International Journal of Biological Sciences|Labels: RAS, pancreatic cancer

The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Rasmt alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Rasmt. Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Rasmt is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Rasmt activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Rasmt. Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Rasmt activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease.

Friday, September 16, 2016 10:23 AM|Jingrong Xian, Huiyuan Shao, Xianchun Chen, Shuaishuai Zhang, Jing Quan, Qin Zou, Hongjun Jin, Ling Zhang|International Journal of Biological Sciences|Labels: ERK, RAS, AML

Acute myeloid leukemia (AML) with mutated nucleophosmin (NPM1) has been defined as a unique subgroup in the new classification of myeloid neoplasm, and the AML patients with mutated NPM1 frequently present extramedullary infiltration, but how NPM1 mutants regulate this process remains elusive. In this study, we found that overexpression of type A NPM1 gene mutation (NPM1-mA) enhanced the adhesive, migratory and invasive potential in THP-1 AML cells lacking mutated NPM1. NPM1-mA had up-regulated expression and gelatinolytic matrix metalloprotease-2 (MMP-2)/MMP-9 activity, as assessed by real-time PCR, western blotting and gelatin zymography. Following immunoprecipitation analysis to identify the interaction of NPM1-mA with K-Ras, we focused on the effect of NPM1-mA overexpression on the Ras/Mitogen-activated protein kinase (MAPK) signaling axis and showed that NPM1-mA increased the MEK and ERK phosphorylation levels, as evaluated by western blotting. Notably, a specific inhibitor of the ERK/MAPK pathway (PD98059), but not p38/MAPK, JNK/MAPK or PI3-K/AKT inhibitors, markedly decreased the cell invasion numbers in a transwell assay. Further experiments demonstrated that blocking the ERK/MAPK pathway by PD98059 resulted in reduced MMP-2/9 protein levels and MMP-9 activity. Additionally, NPM1-mA overexpression had down-regulated gene expression and protein production of tissue inhibitor of MMP-2 (TIMP-2) in THP-1 cells. Furthermore, evaluation of gene expression data from The Cancer Genome Atlas (TCGA) dataset revealed that MMP-2 was overexpressed in AML patient samples with NPM1 mutated and high MMP-2 expression associated with leukemic skin infiltration. Taken together, our results reveal that NPM1 mutations contribute to the invasive potential of AML cells through MMPs up-regulation via Ras/ERK MAPK signaling pathway activation and offer novel insights into the potential role of NPM1 mutations in leukemogenesis.

Thursday, September 15, 2016 11:42 PM|Jin Luo, Yan-Ni Li, Fei Wang, Wei-Ming Zhang, Xin Geng|International Journal of Biological Sciences|Labels: Myc, RAS, CRC, gastric

A global DNA hypomethylation might activate oncogene transcription, thus promoting carcinogenesis and tumor development. S-Adenosylmethionine (SAM) serves as a major methyl donor in biological transmethylation events. The object of this study is to explore the influence of SAM on the status of methylation at the promoter of the oncogenes c-myc, H-ras and tumor-suppressor gene p16 (INK4a), as well as its inhibitory effect on cancer cells. The results indicated that SAM treatment inhibited cell growth in gastric cancer cells and colon cancer cells, and the inhibition efficiency was significantly higher than that in the normal cells. Under standard growth conditions, C-myc and H-ras promoters were hypomethylated in gastric cancer cells and colon cancer cells. SAM treatment resulted in a heavy methylation of these promoters, which consequently downregulated mRNA and protein levels. In contrast, there was no significant difference in mRNA and protein levels of p16 (INK4a) with and without SAM treatment. SAM can effectively inhibit the tumor cells growth by reversing the DNA hypomethylation on promoters of oncogenes, thus down-regulating their expression. With no influence on the expression of the tumor suppressor genes, such as P16, SAM could be used as a potential drug for cancer therapy.

Thursday, September 15, 2016 7:51 PM|Hyunsu Lee, Jae-Ho Lee, Dae-Kwang Kim, In-Jang Choi, Ilseon Hwang, Yu-Na Kang, Shin Kim|International Journal of Medical Sciences|Labels: BRAF, PI3K, RAS

Colorectal cancer is a heterogeneous disorder than arises via multiple distinct pathways, from tubular adenomas (TAs) and sessile serrated adenomas (SSAs), which are clinically, morphologically, and molecularly different. We examined PIK3CA amplification in colorectal precancerous legions, including TAs and SSAs. DNA was isolated from paired normal and tumoral tissues in 64 TAs and 32 SSAs. PIK3CA amplification, KRAS mutation, and BRAF mutation were analyzed by real-time PCR and pyrosequencing. PIK3CA amplification was found in 25% of TAs and 9.4% of SSAs, respectively. KRAS and BRAF mutations were mutually exclusive in both TAs and SSAs. In TAs, PIK3CA amplification was associated with left side and it was mutually exclusive with KRAS mutation. These results suggest that PIK3CA amplification may be early and important event in colorectal carcinogenesis and may drive the development of left-side TAs independently with KRAS mutation.

Wednesday, September 14, 2016 4:23 PM|T. Ruksha|JournalTOCs API - Journal of Investigative Dermatology (875 articles)|Labels: BRAF, RAS, melanoma

507 Clinicopathological features and NRAS gene mutation status in patients with primary cutaneous melanoma
M. Aksenenko T. Ruksha
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S247 -
NRAS oncogene mutations are the second most common mutation type in cutaneous melanoma. Large majority of these mutations affect NRAS exon 3, codons 59, 60,61 or 62. NRAS mutations are often present in melanomas arising from sites of chronic sun damage. The aim of this study was to evaluate NRAS mutations exon 3 frequency in BRAF-negative melanomas. Genomic DNA was extracted from biopsy specimens with suitable percentage of tumor cells. BRAF V600 mutations were estimated by real-time PCR-based allele-specific DNA test.

495 Hyperactive NRAS downstream signaling induces specific transcriptome changes –esiRNA based identification of new therapeutic targets in NRAS mutant melanoma identifies the noncoding RNA 7SL as a major proliferation enhancer
I. Vujic M. Vujic, M. Sanlorenzo, C. Posch, A. Preschitz, R. Esteve-Puig, K. Lai, W. Ho, K. Rappersberger, S. Ortiz-Urda
Journal of Investigative Dermatology, Vol. 136, No. 9 (2016) pp. S245 -
Benign naevi and malignant melanomas both can have oncogenic mutations in the NRAS gene but naevi only rarely progress to cancer. Such NRAS mutations should lead to specific transcriptome changes. The knowledge of these changes can A) identify new therapeutic targets and B) explain why some naevi have NRAS mutations but stay benign. Here, we introduce NRAS(Q61) mutant plasmids in a pool of human melanocytes to overactivate NRAS downstream pathways. We perform deep RNASeq and compare transcriptome changes in melanocytes with and without NRAS mutation.

Wednesday, September 14, 2016 7:55 AM|YAPIJAKIS, C., ADAMOPOULOU, M., TASIOUKA, K., VOUMVOURAKIS, C., STRANJALIS, G.|Anticancer Research current issue|Labels: EGFR, RAS, brain cancer

Background/Aim: A deeper understanding of the complex molecular pathology of brain malignancies is needed in order to develop more effective and targeted therapies of these highly lethal disorders. In an effort to further enlighten the molecular pathology of brain oncogenesis involving the her-2 (erbB-2/neu/ngl)/N-ras/nf1 pathway, we screened the genotypes of specimens from various types of brain tumors. Materials and Methods: The studied specimens included 35 biopsies of four general categories: 13 neuroglial tumors (4 astrocytomas, 2 oligodendrogliomas, 7 glioblastomas multiforme), 14 meningiomas, 3 other nervous system tumors (2 schwannomas, 1 craniopharyngioma) and 5 metastatic tumors (such as lung carcinomas and chronic myelocytic leukemia). Screening for most common mutations in oncogenes her-2, N-ras and tumor suppressor gene nf1 was conducted with molecular hybridization techniques (Southern blotting, dot blot and single-strand conformational polymorphism (SSCP) analysis, respectively), and was confirmed by DNA sequencing. Results: Gene amplification of her-2 was observed in only two cases (6%), namely in one glioblastoma and in one meningioma. Screening of 3 hot spot codons of the N-ras gene (12, 13 and 61) and subsequent DNA sequencing revealed mutations in 19 biopsies encompassing all categories (54%). Screening for mutations in exons of the nf1 gene by SSCP analysis detected a novel nonsense mutation in exon 31 in a unique case of a glioblastoma biopsy (3%) taken from a patient without neurofibromatosis type I. Conclusion: Activated N-ras appears to be a major oncogene in brain oncogenesis, exhibiting the most important role in the her-2/N-ras/nf1 pathway.

Wednesday, September 14, 2016 7:55 AM|NAKAI, Y., ISAYAMA, H., SASAKI, T., TAKAHARA, N., SAITO, K., TAKEDA, T., UMEFUNE, G., SAITO, T., TAKAGI, K., WATANABE, T., HAMADA, T., UCHINO, R., MIZUNO, S., YAMAMOTO, K., KOGURE, H., MATSUBARA, S., YAMAMOTO, N., IJICHI, H., TATEISHI, K., TADA, M., KOIKE, K.|Anticancer Research current issue|Labels: RAS, liver cancer

Aim: The renin–angiotensin system (RAS) was investigated as a target for cancer treatment. Patients and Methods: A total of 287 patients with biliary tract cancer (BTC) receiving chemotherapy were retrospectively studied to evaluate the role of inhibition of RAS by angiotensin system inhibitors (ASIs). Progression-free survival (PFS) and overall survival (OS) were compared between 74 patients with hypertension, on ASIs (ASI group), 50 patients with hypertension not on ASIs (non-ASI with HT group) and 163 patients without hypertension (non-HT group). Interactions between the use of ASIs and various subgroups were explored. Results: The median PFS was 3.6, 3.9 and 4.6 months (p=0.495) and the median OS was 11.6, 10.9 and 13.1 months (p=0.668), respectively. The use of ASIs was not associated with OS (hazard ratio 1.00, p=0.975) and no subgroups with better survival were identified. Conclusion: No survival benefit from ASIs was observed in BTC.

Tuesday, September 13, 2016 11:38 PM|Mingyue Zhu, Yan Lu, Wei Li, Junli Guo, Xu Dong, Bo Lin, Yi Chen, Xieju Xie, Mengsen Li|Journal of Cancer|Labels: RAS, liver cancer

Background: The infection of Hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma(HCC), HBV-X protein(HBx) is able to induce expression of alpha-fetoprotein(AFP) in normal liver cells, and AFP harbors a function to promote malignant transformation of normal liver cells, but the role AFP playing in malignant behaviors of HCC cells is still unclear.

Methods: Fifty-six liver tissue samples were collected from the clinical patients through hepatectomy(include normal liver tissues, HBV-related hepatitis liver tissues and HBV-related HCC tissues), and diagnosis of these tissues by pathology section, expression of AFP, Ras and CXCR4 were evidenced by immunohisochemical staining and Western blotting; The proliferation of human normal liver cells line L-02 cells and human hepatoma cells line, HLE cells(non AFP-producing) were performed by MTT method; Repaired capacity of L-02 and HLE cells were compared by wound healing assay; Migration and invasion of these cells were analyzed by Transwell chamber assay; HBx expressed vectors(pcDNA3.1-HBx) were constructed and transfected into L-02 and HLE cells, effects of pcDNA3.1-HBx on the malignant behaviors were also detected by MTT, Transwell chamber assay and the expression of AFP, Ras and CXCR4 were evidenced by Western blotting.

Results: we found that expression of AFP, Ras and CXCR4 in HBV-related HCC and lymph nodes metastasis tissues were significantly elevated compared with HBV-related HCC, non metastasis tissues and HBV-related hepatitis tissues; Expression of AFP, Ras and CXCR4 in HBV-related hepatitis tissues were significantly enhanced compared with normal liver tissues; The growth ratio, migratory and invasive ability, expression of AFP, Ras and CXCR4 of the cells were outstanding promoted while L-02 and HLE cells were transfected with pcDNA3.1-HBx vectors. The proliferation ratio, migration and invasion ability, and expression of Ras and CXCR4 were significantly inhibited while L-02-X and HLE-X cells(stably transfected with pcDNA3.1-HBx) were silenced AFP expression by AFP-siRNA.

Conclusions: HBx through stimulating expression of AFP to promote malignant behaviors of human normal liver cells and HCC cells; AFP maybe used as a novel biotarget for therapeutics of HCC patients.

Tuesday, September 13, 2016 11:38 PM|Jinlong Li, Jie Luo, Dongsheng Gu, Feilong Jie, Nana Pei, Andrew Li, Xinglu Chen, Yanling Zhang, Hongyan Du, Baihong Chen, Weiwang Gu, Colin Sumners, Hongwei Li|Journal of Cancer|Labels: RAS, prostate cancer

The renin-angiotensin system (RAS) plays important roles in tumorigenesis and is involved with several hallmarks of cancer. Evidence shows that angiotensin II (AngII) type 1 receptor (AT1R) blockers may be associated with improved outcome in prostate cancer patients. Furthermore, our previous studies indicate that increased expression of Ang II type 2 receptor (AT2R) alone induced apoptosis in human prostate cancer lines, an effect that did not require Ang II. This study aimed to investigate the effects of AT2R on tumor growth in vivo and we hypothesized that AT2R over-expression would inhibit proliferation and induce apoptosis in vivo. Human prostate cancer DU145 xenograft mouse model was used to assess the effect of AT2R on tumor growth in vivo. Mice bearing a palpable tumor were chosen and divided randomly into three treatment groups: AT2R, GFP, and PBS. Then we directly injected into the xenograft tumors of the mice every three days with recombinant adenoviruses encoding AT2R (Ad5-CMV-AT2R-EGFP), EGFP (Ad5-CMV-EGFP) and PBS, respectively. The tumor sizes of the tumor bearing mice were then measured. Immunohistochemical Ki-67 staining and TUNEL assay were performed to examine the inhibitory effect of AT2R on tumor cell proliferation. The results showed that AT2R overexpression can inhibit tumor growth of prostate cancer in vivo by inhibiting proliferation and inducing apoptosis of tumor cells. GADD45A is involved in the AT2R-induced antitumor activity. This suggests that AT2R is a potentially useful gene for prostate gene therapy.

Tuesday, September 13, 2016 8:19 PM|A. Orlandi, M. Di Salvatore, C. Bagalà, M. Basso, A. Strippoli, F. Plastino, M.A. Calegari, A. Cassano, A. Astone, C. Barone|Journal of Cancer (RSS 2.0)|Labels: RAS, CRC

Introduction: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance.

Material and Methods: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor.

Results: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line.

Conclusion: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1.

Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: RAS, CRC
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Passot, G.; Chun, Y.S.; Kopetz, S.E.;...
Introduction For patients with stage IV colorectal cancer, the liver is the most common site of distant metastases. Advances in modern chemotherapy and targeted agents have significantly improved response and survival rates for patients with color...
Tuesday, September 13, 2016 4:20 PM|ClinicalKey Latest Issue: European Journal of Surgical Oncology|Labels: RAS, gastric
European Journal of Surgical Oncology, Volume 42, Issue 9, 2016 Sep | Polom, K.; Pascale, V.; Ferrara, F.;...
Background : Gastric cancer (GCacrnm1) molecular division and different mutations in specific genes seems to be a key to implement targeted therapies and tailored surgical approach. An example of an important mutation in gastrointestinal tract mal...
Sunday, September 4, 2016 4:00 PM|Kun-Hung Shen, Chien-Feng Li, Lan-Hsiang Chien, Cheng-Hao Huang, Chia-Cheng Su, Alex C. Liao, Ting-Feng Wu|Cancer Science|Labels: GAL, Jnk, RAS, bladder cancer
Human galectin-1 is a member of the galectin family, proteins with conserved carbohydrate-recognition domains that bind galactoside. Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. However, detailed descriptions of the function of galectin-1 in urinary bladder urothelial carcinoma have not been reported. Our previous cohort investigation showed that galectin-1 is associated with tumor invasiveness and is a possible independent prognostic marker of urinary bladder urothelial carcinoma. The present study aimed to clarify the relevance of galectin-1 expression level to tumor progression and invasion. In order to decipher a mechanism for the contribution of galectin-1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin-1 expression by shRNA. Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity. Extensive signaling pathway studies indicated that galectin-1 participated in bladder cancer cell invasion by mediating the activity of MMP9 through the Ras–Rac1–MEKK4–JNK–AP1 signaling pathway. Our functional analyses of galectin-1 in urinary bladder urothelial carcinoma provided novel insights into the critical role of galectin-1 in tumor progression and invasion. These results revealed that silencing the galectin-1-mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy. Galectin-1 participated in bladder cancer cell invasion through mediating the activity of matrix metalloproteinase 9 via Ras–Rac1–MAP/ERK kinase kinase 4–c-Jun N-terminal protein kinase–AP1 signaling pathway.
Wednesday, August 31, 2016 11:00 PM|Hashimoto, Daisuke; Arima, Kota; Yokoyama, Naomi; Chikamoto, Akira; Taki, Katsunobu; Inoue, Risa; Kaida, Takayoshi; Higashi, Takaaki; Nitta, Hidetoshi; Ohmuraya, Masaki; Hirota, Masahiko; Beppu, Toru; Baba, Hideo|Pancreas - Current Issue|Labels: RAS, pancreatic cancer
imageObjectives: Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma. Methods: Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing. Results: Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes. Conclusions: Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.
Wednesday, August 31, 2016 10:05 PM|Li, F., Liu, X., Sampson, J. H., Bigner, D. D., Li, C.-Y.|Cancer Research recent issues|Labels: RAS, telomerase, brain cancer
Cancer stem-like cells (CSC) are thought to drive brain cancer, but their cellular and molecular origins remain uncertain. Here, we report the successful generation of induced CSC (iCSC) from primary human astrocytes through the expression of defined genetic factors. Combined transduction of four factors, Myc, Oct-4, p53DD, and Ras, induced efficient transformation of primary human astrocytes into malignant cells with powerful tumor-initiating capabilities. Notably, transplantation of 100 transduced cells into nude mice was sufficient for tumor formation. The cells showed unlimited self-renewal ability with robust telomerase activities. In addition, they expressed typical glioma stem-like cell markers, such as CD133, CD15, and CD90. Moreover, these cells could form spheres in culture and differentiate into neuron-like, astrocyte-like, and oligodendrocyte-like cells. Finally, they also displayed resistance to the widely used brain cancer drug temozolomide. These iCSCs could provide important tools for studies of glioma biology and therapeutics development. Cancer Res; 76(17); 5143–50. ©2016 AACR.
Sunday, August 14, 2016 10:05 PM|Harbst, K., Lauss, M., Cirenaȷwis, H., Isaksson, K., Rosengren, F., Torngren, T., Kvist, A., Johansson, M. C., Vallon–Christersson, J., Baldetorp, B., Borg, A., Olsson, H., Ingvar, C., Carneiro, A., Jonsson, G.|Cancer Research recent issues|Labels: BRAF, RAS, melanoma
Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%–38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P < 0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome. Cancer Res; 76(16); 4765–74. ©2016 AACR.
Sunday, August 14, 2016 10:05 PM|Parasido, E. M., Sripadhan, P., Schlegel, R., Pishvaian, M. J., Brody, J., Winter, J., Albanese, C.|Clinical Cancer Research recent issues|Labels: P53, RAS, pancreatic cancer

Background: Pancreatic adenocarcinoma (PA) is the fourth leading cause of cancer related death in the USA. Patients diagnosed with this disease can expect a 1-year survival rate of approximately 10%. One of the main reasons of the high mortality observed within PA is failure on first-line therapies. Current PA treatment involves Gemcitabine, a nucleoside analog that showed improvement in overall survival. Recently this drug has been used in combination with nab-paclitaxel, 5-FU, Erlotinib and MEK inhibitors. However, a growing number of patients have shown resistance to these regimes. A more comprehensive understanding of resistance mechanisms will enhance treatment choice and clinical responses, and this remains an area of intense investigation. However much of the data available on PA drug targets and efficacy come from commercially available pancreatic cell lines, a main limitation in PA research, as these lines do not accurately represent a given patients' tumor, underscoring the need for the development and use of patient-specific primary epithelial PA cells. In our current study we present the use of patient-derived primary PA cells as a model system for basic and translational research as well as personalized therapeutic approaches.

Methods: Patients' biopsies were collected after surgery and long-term cultures of PA cells were established using the conditional reprogramming of cells (CRC) approach. To date, six primary lines have been continuous culture for over 6 month. KRAS and p53 sequencing verified the PA origin of both the patient sample and the matched CRC lines. CRC karyotyping was also performed to confirm the absence of normal cells as well as to validate the long-term genomic integrity of the lines in culture. In order to evaluate patient-specific differences in treatment response, the IC50's for gemcitabine, nab-paclitaxel (Abraxane) and the MEK inhibitor, Trametinib, were determined. To better understand treatment resistance mechanisms, new drug resistance approaches were developed and multiple drug-resistant clones per primary cell line were established, and their resistance verified. Gemcitabine activity was also evaluated in combination with Abraxane and Trematenib in both parental and resistant-clone cell lines. In addition, novel three-dimensional (3D) organoid cultures have been established from the two dimensional (2D) CRC cultures in order to verify the constancy of the model.

Results: We established KRAS-mutant primary cell lines derived from patients' PA specimens. The cell lines' karyotype showed stability over multiple passages covering more than 6 months in continuous 2D culture. Five Abraxane resistant clones have been derived to date from two different parent cell lines and two gemcitabine resistant clones derived from one of these cell lines. The clones tested were 3 to 1000 times less sensitive to the drugs when compared to the parents. Notably, the Abraxane resistant clones also showed a greater resistance to Gemcitabine as compared to the parent line. In addition, the PA lines also showed an overall increasing sensitivity to Gemcitabine when pre- or co-treated with Trematenib. Molecular and genetic analyses are being performed to identify potential biomarkers of high therapeutic value.

Conclusion: Taken together, the ease of culture, the genetic stability, the medium to high throughput ability to identify differences between patients sensitivity to FDA approved drugs, all confirm the power of this technology for on-demand in vitro use in PA research. Our approach now enables the high-resolution experiments necessary to better understand the underlying drug sensitivity and resistance mechanisms that directly affect clinical outcomes.

Citation Format: Erika M. Parasido, Praathibha Sripadhan, Richard Schlegel, Michael J. Pishvaian, Jonathan Brody, Jordan Winter, Christopher Albanese. Patient-derived Pancreatic Adenocarcinoma cells: A new model system to define chemotherapy resistance mechanisms and to improve targeted personalized treatment. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B15.

CONCLUSIONSThese data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Friday, August 12, 2016 12:58 PM|Bartolini, A., Cardaci, S., Lamba, S., Oddo, D., Marchio, C., Cassoni, P., Amoreo, C. A., Corti, G., Testori, A., Bussolino, F., Pasqualini, R., Arap, W., Cora, D., Di Nicolantonio, F., Marchio, S.|Clinical Cancer Research Online First Articles|Labels: RAS, CRC

Purpose: KRAS mutations confer adverse prognosis to colorectal cancer, and no targeted therapies have shown efficacy in this patient subset. Paracrine, nongenetic events induced by KRAS-mutant tumor cells are expected to result in specific deregulation and/or relocation of tumor microenvironment (TME) proteins, which in principle can be exploited as alternative therapeutic targets.

Experimental Design: A multimodal strategy combining ex vivo/in vitro phage display screens with deep-sequencing and bioinformatics was applied to uncover TME-specific targets in KRAS-mutant hepatic metastasis from colorectal cancer. Expression and localization of BCAM and LAMA5 were validated by immunohistochemistry in preclinical models of human hepatic metastasis and in a panel of human specimens (n = 71). The antimetastatic efficacy of two BCAM-mimic peptides was evaluated in mouse models. The role of BCAM in the interaction of KRAS-mutant colorectal cancer cells with TME cells was investigated by adhesion assays.

Results: BCAM and LAMA5 were identified as molecular targets within both tumor cells and TME of KRAS-mutant hepatic metastasis from colorectal cancer, where they were specifically overexpressed. Two BCAM-mimic peptides inhibited KRAS-mutant hepatic metastasis in preclinical models. Genetic suppression and biochemical inhibition of either BCAM or LAMA5 impaired adhesion of KRAS-mutant colorectal cancer cells specifically to endothelial cells, whereas adhesion to pericytes and hepatocytes was unaffected.

Conclusions: These data show that the BCAM/LAMA5 system plays a functional role in the metastatic spreading of KRAS-mutant colorectal cancer by mediating tumor–TME interactions and as such represents a valuable therapeutic candidate for this large, currently untreatable patient group. Clin Cancer Res; 1–11. ©2016 AACR.

Sunday, July 31, 2016 10:05 PM|Ji, S., Qin, Y., Liang, C., Huang, R., Shi, S., Liu, J., Jin, K., Liang, D., Xu, W., Zhang, B., Liu, L., Liu, C., Xu, J., Ni, Q., Chiao, P. J., Li, M., Yu, X.|Clinical Cancer Research recent issues|Labels: RAS, pancreatic cancer

Purpose: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras–Raf–MEK–ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.

Experimental Design: Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo. Finally, gene expression profiling was performed to identify core signaling pathways.

Results: The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro. Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose (18F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc–dependent manner.

Conclusions: Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950–60. ©2016 AACR.

Sunday, July 31, 2016 6:00 PM|Falcone, A.|The Oncologist Subject Collection: Gastrointestinal Cancer|Labels: BRAF, RAS, CRC
Introduction.Right- and left-sided colorectal cancers (CRCs) differ in clinical and molecular characteristics. Some retrospective analyses suggested that patients with right-sided tumors derive less benefit from anti-epidermal growth factor receptor (EGFR) antibodies; however, molecular selection in those studies was not extensive. Patients and Methods.Patients with RAS and BRAF wild-type metastatic CRC (mCRC) who were treated with single-agent anti-EGFRs or with cetuximab-irinotecan (if refractory to previous irinotecan) were included in the study. Differences in outcome between patients with right- and left-sided tumors were investigated. Results.Of 75 patients, 14 and 61 had right- and left-sided tumors, respectively. None of the right-sided tumors responded according to RECIST, compared with 24 left-sided tumors (overall response rate: 0% vs. 41%; p = .0032), and only 2 patients with right-sided tumors (15%) versus 47 patients with left-sided tumors (80%) achieved disease control (p < .0001). The median duration of progression-free survival was 2.3 and 6.6 months in patients with right-sided and left-sided tumors, respectively (hazard ratio: 3.97; 95% confidence interval: 2.09-7.53; p < .0001). Conclusion.Patients with right-sided RAS and BRAF wild-type mCRC seemed to derive no benefit from single-agent anti-EGFRs. Implications for PracticeRight- and left-sided colorectal tumors have peculiar epidemiological and clinicopathological characteristics, distinct gene expression profiles and genetic alterations, and different prognoses. This study assessed the potential predictive impact of primary tumor site with regard to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment in patients with RAS and BRAF wild-type metastatic colorectal cancer. The results demonstrated the lack of activity of anti-EGFRs in RAS and BRAF wild-type, right-sided tumors, thus suggesting a potential role for primary tumor location in driving treatment choices.
Thursday, July 28, 2016 7:56 AM|Veneziale, B., Huang, L., Li, X., Zhao, Q., Zhao, C., Osgood, R., Cowell, J., Rosengren, S., Parise, J., Wei, G., Phan, K., Connor, R., Rowe, S., Keller, G., Frost, G., Maneval, D., Thompson, C., Shepard, M., Thanos, C.|Cancer Research recent issues|Labels: BRAF, EGFR, RAS
The epidermal growth factor (EGF) signaling pathway relies on recognition by its receptor, EGFR, and subsequent downstream signaling by the KRAS and BRAF proteins to relay proper proliferative, migratory, and angiogenic functions. Cancers with activating KRAS or BRAF mutations are resistant to EGFR targeting agents and correspond to a significant unmet medical need. We hypothesized that an anti-EGFR antibody-drug conjugate (ADC) could be active against KRAS or BRAF mutated tumors, due to the cytotoxic mechanism of the ADC warhead. In an effort to eliminate the known dermal toxicity associated with anti-EGFR therapy, and to mitigate potential toxicities associated with treatment by an anti-EGFR ADC, we wished to engineer an antibody with enhanced specificity towards EGFR in the tumor microenvironment (TME) and attenuated binding to EGFR in normal tissue. This was achieved by screening a library of antibody variants (based on cetuximab) in a spatially addressed manner for binding to a recombinant version of the EGFR extracellular domain (EGFRECD) in two separate ELISA reaction conditions. High affinity binding to the EGFRECD was desired in the first condition, which approximated the physicochemical properties of the TME (acidic pH, high lactic acid concentration, 25% human serum). In the second assay condition, which approximated mAb binding to EGFRECD in normal tissue (neutral pH, low lactic acid concentration, 25% human serum), attenuated binding affinity was desired. We identified a lead mAb variant, cMab-1501, which possessed several fold reduced binding to EGFRECD in the neutral pH, low lactic acid condition, when compared to EGFRECD binding in the low-pH, high lactic acid, assay condition. To evaluate enhanced specificity for binding to EGFR in vivo, cMab-1501 was compared to cetuximab for binding to both human donor foreskin xenografts and human A431 tumor xenografts, using a DyLight 755 conjugated version of each antibody, and subsequent fluorescence detection with a Caliper IVIS system. cMab-1501 and cetuximab demonstrated relatively comparable binding towards human A431 tumor xenografts in vivo. In addition, cetuximab bound relatively equally between human tumor xenografts and human skin grafts. However, no binding to EGFR in the human skin graft was detected for cMab-1501 over all days measured; suggesting that cMab-1501 was highly specific for binding to EGFR in the TME. We next generated an cMab-1501 based ADC (antibody-drug conjugate), via maleimide chemistry carrying a protease cleavable valine-citrulline-p-aminobenzyloxycarbonyl monomethylauristatin E (vcPAB-MMAE) cytotoxic moiety, forming a cMab-1501-vcPAB-MMAE conjugate. Both the conjugated and un-conjugated versions of cMab-1501 were rapidly internalized by EGFR positive MDA-MB-231M tumor cells over several hours. In tumor xenograft models, the TME-specific anti-EGFR ADC demonstrated complete tumor regressions against two human EGFR overexpressing tumor types, MDA-MB-231M (TNBC, KRAS G13D) and HT-29 (CRC, BRAF V600E). In both in vivo models, tumors were resistant to treatment by cetuximab. These data suggest that it is possible to engineer a monoclonal antibody with enhanced specificity for its target within the TME and that an ADC-based approach could be utilized as potential treatment of EGFR overexpressing tumors with KRAS or BRAF mutations.Citation Format: Bob Veneziale, Lei Huang, Xiaoming Li, Qiping Zhao, Chunmei Zhao, Ryan Osgood, Jessica Cowell, Sanna Rosengren, Jason Parise, Ge Wei, Kim Phan, Robert Connor, Steve Rowe, Gilbert Keller, Gregory Frost, Dan Maneval, Curtis Thompson, Michael Shepard, Christopher Thanos. A tumor microenvironment specific EGFR targeting antibody-drug conjugate promotes regression in KRAS or BRAF mutant tumors. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B32.
Thursday, July 28, 2016 7:56 AM|Metz, H. E., Kargl, J., Busch, S., Kim, K.-H., Houghton, M.|Cancer Research recent issues|Labels: RAS, STAT, lung cancer
Lung cancer is the leading cause of cancer deaths worldwide. In the United States alone, lung cancer accounts for ~160,000 deaths per year while the five-year survival rate remains stagnant at ~15%. Lung adenocarcinoma (ADCA) accounts for over 50% of non-small lung cancer cases. Within this subset, K-ras is the most common activating mutation accounting for ~35% of cases. Kras mutant tumors have remained a largely un-targetable subtype and a better understanding of the signaling pathway involved in the different ADCA subtypes will be necessary for the development of therapeutics. Insulin Receptor Substrate-1 (IRS-1) is a signaling adaptor protein that interfaces with many of the pathways that are activated in lung cancer. We have undertaken a controlled study of this protein within the context of lung ADCA. Analysis of a well-annotated human lung ADCA TMA (n=136) revealed that positive IRS-1 staining provided a 75-month median survival advantage among all ADCA cases (p=0.01) and an 81-month median advantage within the K-ras subtype (p=0.006). EGFR and non-K-ras/non-EGFR cases did not display differences. To focus in on the K-ras subtype, we generated LSL-K-ras/IRS-1fl/fl mice and studied them over a time course. LSL-K-ras/IRS-1-/- mice displayed highly significant early mortality (p<0.0001) and increased tumor burden when compared to LSL-K-ras/IRS-1+/+ controls (p<0.01). Interestingly, IRS-1 loss in tumor cells generated a robust immune response. The bronchial alveolar lavage fluid of LSL-K-ras/IRS-1-/- mice showed increased immune infiltration, most prominently neutrophilic (5 times higher). Significant increases in many immune cell-recruiting chemokines were observed in the LSL-K-ras/IRS-1-/- mice compared to controls including CCL2, CCL3, CCL4, CXCL1, CXCL2 and CXCL5. Surprisingly, an array of IRS-1 silenced A549 cells versus controls displayed no change in CC/CXC chemokine production. We decided to investigate which factor could be missing in our in vitro system that is necessary for activation of this chemokine response. IL-17 and IL-22 producing cells, which are present at sites of tumor in human lung cancer cases and LSL-K-ras mice are known to induce CC/CXC chemokine responses. The JAK/STAT pathway is also implicated in this response. We found that loss of IRS-1 increases pSTAT3 production in vivo and in vitro in the presence of IL-22. Finally, we treated LSL-K-ras/IRS-1-/- and LSL-K-ras/IRS-1+/+ controls with a JAK inhibitor (AZD1480). A significant reduction in tumor burden and chemokine response was observed in both genotypes, with the most pronounced response in the LSL-K-ras/IRS-1-/- group. K-ras mutant, IRS-1-low patients represent ~40% of K-ras mutant lung ADCA patients. The phenotype of this group of patients is counter-intuitive in that IRS-1 typically functions in a pro-growth manner. In the setting of certain oncogenic drivers, however, IRS-1 plays an opposing role to this in which its presence actually maintains homeostasis. This work provides evidence that JAK inhibition may be a viable therapeutic option for these patients as well as describes a novel role for IRS-1 as a mediator of immune cell recruitment in lung adenocarcinoma.Citation Format: Heather E. Metz, Julia Kargl, Stephanie Busch, Kyoung-Hee Kim, McGarry Houghton. Novel pro-host role for insulin receptor substrate-1 in lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B26.
Thursday, July 28, 2016 2:00 AM|Merck News Releases|Attachments|Labels: RAS, CRC, biomarker diagnostic
Darmstadt, Germany, July 28, 2016 – Merck, a leading science and technology company, today announced that it has signed a new collaboration agreement with Xiamen based Amoy Diagnostics Co., Ltd. (AmoyDx) for the development and commercialization of a new liquid biopsy RAS biomarker test for patients with metastatic colorectal cancer (mCRC). The test will be developed using AmoyDx real-time polymerase chain reaction (PCR) technology, ADx-SuperARMS®, and will be made available in China in 2017.
Wednesday, July 27, 2016 11:11 AM|PLOQUIN, A., ZERIMECH, F., ESCANDE, F., ADENIS, A., GIRAUD, C., GASNAULT, L., BOURGEOIS, V., DESAUW, C., HEBBAR, M.|Anticancer Research recent issues|Labels: RAS, CRC

Background/Aim: We previously identified three clinical predictive factors of efficacy of cetuximab-irinotecan. Here, we analyzed the clinical characteristics of patients with metastatic colorectal cancer (CRC) in order to detect potent correlations with KRAS mutations. Patients and Methods: We conducted a retrospective, multicenter study between 2008 and 2012. We included patients with metastatic colorectal adenocarcinomas, previously treated by irinotecan, and with an available KRAS mutation test. Results: We included 299 patients. The median age was 60 years; the median number of metastatic sites was 2. One hundred and eight patients (36.1%) had a previous objective response to irinotecan. The median interval between diagnosis and irinotecan discontinuation was 1.94 years. A KRAS mutation was detected in 133 patients (44.5%). In univariate and multivariate analyses, none of the assessed factors was associated with the presence of a KRAS mutation. Conclusion: No easily clinically assessable parameter was significantly associated with KRAS mutations in patients with colorectal cancer.

Tuesday, July 26, 2016 10:40 AM|Trinh, A., Trumpi, K., de Sousa e Melo, F., Wang, X., de Jong, J. H., Fessler, E., Kuppen, P. J. K., Reimers, M. S., Swets, M., Koopman, M., Nagtegaal, I. D., Jansen, M., Hooijer, G. K. J., Offerhaus, G. J., Kranenburg, O., Punt, C. J. A., Medema, J. P., Markowetz, F., Vermeulen, L.|Clinical Cancer Research Online First Articles|Labels: RAS, CRC

Purpose: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer (CRC) with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles towards widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular CRC subtyping in a multi-center study. Experimental Design: Tissue microarrays from 1076 CRC patients from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1 and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semi-quantitative pathologist scoring of the cores as input, and applied to three independent clinical cohorts. Results: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular CRC subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild type metastatic cancers of the canonical epithelial-like subtypes. Conclusion: This study shows that a practical and robust immunohistochemical-assay can be employed to identify molecular CRC subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of CRC samples, both in the format of an automated image analysis pipeline to score tumour core staining, and as a classifier based on semi-quantitative pathology scoring.

Tuesday, July 12, 2016 10:19 AM|Onclive Colorectal Cancer Articles|Labels: RAS, CRC
The debate between the phase III CALGB/SWOG 80405 and FIRE-3 studies has been settled, as findings of a retrospective analysis of 80405 show that tumor location is significant in determining survival outcomes for patients with KRAS wild-type metastatic colorectal cancer.
Monday, July 4, 2016 8:06 AM|News-Medical.Net Gastrointestinal Cancer News Feed|Comments|Labels: RAS, CRC
Merck, a leading science and technology company, will present data at the ESMO 18th World Congress on Gastrointestinal Cancer from the pivotal Phase III TAILOR study in patients from China, the first prospective trial to evaluate an anti-EGFR antibody in the first-line therapy of patients with RAS wild-type metastatic colorectal cancer (mCRC).
Monday, July 4, 2016 1:29 AM|Unknown Author|Pharmafile - ESMO|Comments|Labels: EGFR, RAS, CRC

Merck said late-stage trials for its Erbitux (cetuximab) in combination with Folfox significantly improved progression free survival in metastatic colorectal cancer (mCRC). 

The findings were announced at the ESMO 18th World Congress on Gastrointestinal Cancer (WCGC) and come from the pivotal Phase III study in patients from China, the first prospective trial to evaluate an anti-EGFR antibody in the first-line therapy of patients with RAS wild-type metastatic colorectal cancer. 

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Thursday, June 30, 2016 10:05 PM|Redig, A. J., Capelletti, M., Dahlberg, S. E., Sholl, L. M., Mach, S., Fontes, C., Shi, Y., Chalasani, P., Jänne, P. A.|Clinical Cancer Research recent issues|Labels: RAS, lung cancer

Purpose: NF1 is a tumor suppressor that negatively regulates Ras signaling. NF1 mutations occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers with comparison to tumors with KRAS mutations.

Experimental Design: Between July 2013 and October 2014, 591 non–small cell lung cancer (NSCLC) tumors underwent targeted next-generation sequencing in a 275 gene panel that evaluates gene mutations and genomic rearrangements. NF1 and KRAS cohorts were identified, with subsequent clinical and genomic analysis.

Results: Among 591 patients, 60 had NF1 mutations (10%) and 141 (24%) had KRAS mutations. 15 NF1 mutations (25%) occurred with other oncogenic mutations [BRAF (2); ERBB2 (2); KRAS (9); HRAS (1); NRAS (1)]. There were 72 unique NF1 variants. NF1 tumor pathology was diverse, including both adenocarcinoma (36, 60%) and squamous cell carcinoma (10, 17%). In contrast, KRAS mutations occurred predominantly in adenocarcinoma (136, 96%). Both mutations were common in former/current smokers. Among NF1 tumors without concurrent oncogenic alterations, TP53 mutations/2-copy deletions occurred more often (33, 65%) than with KRAS mutation (46, 35%; P < 0.001). No difference between cohorts was seen with other tumor suppressors.

Conclusions: NF1 mutations define a unique population of NSCLC. NF1 and KRAS mutations present in similar patient populations, but NF1 mutations occur more often with other oncogenic alterations and TP53 mutations. Therapeutic strategies targeting KRAS activation, including inhibitors of MAP kinase signaling, may warrant investigation in NF1 mutant tumors. Tumor-suppressor inactivation patterns may help further define novel treatment strategies. Clin Cancer Res; 22(13); 3148–56. ©2016 AACR.

Thursday, June 30, 2016 10:05 PM|Kitai, H., Ebi, H., Tomida, S., Floros, K. V., Kotani, H., Adachi, Y., Oizumi, S., Nishimura, M., Faber, A. C., Yano, S.|Cancer Discovery recent issues|Labels: AKT, MEK, RAS, lung cancer

KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.

Significance: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non–small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754–69. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 681

Thursday, June 30, 2016 10:05 PM|Unknown Author|Cancer Discovery recent issues|Labels: BRAF, RAS

In a phase I trial, BGB-283, which targets the RAF family of proteins, was found to be safe and tolerable—and effective—in treating patients with a variety of solid tumors harboring mutations in BRAF, KRAS, and NRAS.

Thursday, June 30, 2016 10:05 PM|Kim, E., Ilic, N., Shrestha, Y., Zou, L., Kamburov, A., Zhu, C., Yang, X., Lubonja, R., Tran, N., Nguyen, C., Lawrence, M. S., Piccioni, F., Bagul, M., Doench, J. G., Chouinard, C. R., Wu, X., Hogstrom, L., Natoli, T., Tamayo, P., Horn, H., Corsello, S. M., Lage, K., Root, D. E., Subramanian, A., Golub, T. R., Getz, G., Boehm, J. S., Hahn, W. C.|Cancer Discovery recent issues|Labels: PI3K, RAS

Cancer genome characterization efforts now provide an initial view of the somatic alterations in primary tumors. However, most point mutations occur at low frequency, and the function of these alleles remains undefined. We have developed a scalable systematic approach to interrogate the function of cancer-associated gene variants. We subjected 474 mutant alleles curated from 5,338 tumors to pooled in vivo tumor formation assays and gene expression profiling. We identified 12 transforming alleles, including two in genes (PIK3CB, POT1) that have not been shown to be tumorigenic. One rare KRAS allele, D33E, displayed tumorigenicity and constitutive activation of known RAS effector pathways. By comparing gene expression changes induced upon expression of wild-type and mutant alleles, we inferred the activity of specific alleles. Because alleles found to be mutated only once in 5,338 tumors rendered cells tumorigenic, these observations underscore the value of integrating genomic information with functional studies.

Significance: Experimentally inferring the functional status of cancer-associated mutations facilitates the interpretation of genomic information in cancer. Pooled in vivo screen and gene expression profiling identified functional variants and demonstrated that expression of rare variants induced tumorigenesis. Variant phenotyping through functional studies will facilitate defining key somatic events in cancer. Cancer Discov; 6(7); 714–26. ©2016 AACR.

See related commentary by Cho and Collisson, p. 694.

This article is highlighted in the In This Issue feature, p. 681

Monday, June 27, 2016 10:52 AM|YAMAGUCHI, T., IWASA, S., NAGASHIMA, K., IKEZAWA, N., HAMAGUCHI, T., SHOJI, H., HONMA, Y., TAKASHIMA, A., OKITA, N., KATO, K., YAMADA, Y., SHIMADA, Y.|Anticancer Research recent issues|Labels: RAS, CRC

Background/Aim: Panitumumab and cetuximab are known to be effective treatments for KRAS wild-type metastatic colorectal cancer (mCRC). However, it remains unclear which of these two biologic agents confers the greatest benefit when combined with irinotecan in patients with KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan. Patients and Methods: Data, from 139 patients who received panitumumab or cetuximab, in combination with irinotecan, for KRAS wild-type mCRC previously treated with fluoropyrimidine, oxaliplatin and irinotecan were analyzed. The efficacy and safety of panitumumab plus irinotecan was compared to that of cetuximab plus irinotecan. Results: Baseline characteristics of the panitumumab plus irinotecan (n=42) and cetuximab plus irinotecan (n=97) groups were similar. Among patients with measurable lesions, the response rate was 34% in the panitumumab plus irinotecan group and 20% in the cetuximab plus irinotecan group. Median progression-free survival (PFS) was 4.3 and 5.7 months in the panitumumab and cetuximab groups, respectively. Median overall survival was 13.6 months with panitumumab and 11.2 months with cetuximab. Conclusion: Panitumumab plus irinotecan was well-tolerated and displayed a similar level of efficacy to that of cetuximab plus irinotecan.

Tuesday, June 7, 2016 8:29 AM|Gina M. DeNicola et al.|Department of Surgery Faculty Papers|Labels: RAS, ROS

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.

Tuesday, May 31, 2016 11:00 PM|Zhang, Lingyun; Zhan, Xin; Yan, Dingding; Wang, Zhihua|International Journal of Gynecological Cancer - Most Popular Articles|Labels: RAS, cervical cancer
imageObjective: The aims of this study were to discover if increased circulating microRNA-21 (miR-21) expression in serum is associated with lymph node metastasis in patients with cervical cancer and look further into the molecular mechanism of these. Whole-blood samples from 89 patients who have been histopathologically confirmed as having cervical cancer and 20 control subjects were collected, and then the association between lymph node metastasis and the level of circulating miR-21 was compared. Then cervical cancer cell lines HeLa (HPV-18 DNA+, E6/E7RNA+) and HT-3 (HPV DNA−, E6/E7RNA−) were used to confirm the interaction between miR-21 and RASA1. The role of RASA1 in cervical cancer cell migration was also studied in HeLa. Increased circulating miR-21 expression in serum is associated with lymph node metastasis in patients with cervical cancer. MicroRNA-21 reduces RASA1 expression in cervical cancer cell lines and promotes cervical cancer cell migration via RASA1. Furthermore, Ras-induced epithelial-mesenchymal transition contributes to miR-21/RASA1 axis promoting cervical cancer cell migration. Circulating miR-21 in serum could be a promising biomarker in auxiliary diagnosis of lymph node metastasis in cervical cancer, and inhibition of miR-21/RASA1 axis could be a possible strategy to restrain migration of cervical cancer.
Tuesday, May 31, 2016 2:39 PM|Unknown Author|Attachments|Labels: RAS, melanoma
In a preview of ASCO melanoma studies, the NEMO results suggest that binimetinib is reasonable for NRAS-mutated melanoma, and combo regimens continue to show strong outcomes, reports Dr Jeffrey Weber.
Thursday, April 28, 2016 9:59 AM|OGAWA, M., ANAN, T., SUZUKI, T., OKUMA, M., ICHIHARA, K., HASEGAWA, T., YOSHIDA, K., YANAGA, K.|Anticancer Research recent issues|Labels: RAS, CRC

Aim: This prospective study was designed to evaluate the tolerability and the efficacy of bi-weekly SOX (S-1 and oxaliplatin)+cetuximab as first-line chemotherapy for wild-type K-RAS metastatic colorectal cancer. Patients and Methods: We studied patients with previously untreated, unresectable, advanced or recurrent colorectal cancer who were treated in our hospital between October 2010 and March 2013. Their performance status (PS) was 0 to 1. Cetuximab was combined with S-1 and oxaliplatin (SOX+cetuximab). S-1 was given orally at a dose of 40 mg/m2 (40-60 mg, calculated according to body surface area) twice daily after meals for 2 weeks, followed by a 2-week rest (course 1). Oxaliplatin (85 mg/m2) was given on days 1 and 15 of each course. Cetuximab was administered on days 1 (400 mg/m2), 8 (250 mg/m2) and 15 (500 mg/m2) of course 1, followed by every 2 weeks (500 mg/m2) thereafter. Results: The study group comprised of 18 patients. The mean age was 61 (range=32-72) years, the male:female ratio was 10:8 and the PS was 0 in 12 patients and 1 in 6 patients. The median number of administered courses was 6 (range=2-12). The treatment response was complete response (CR) in 2 and partial response (PR) in 10 (response rate=67% (12/18 patients)). The minimum number of treatment courses until a PR was 2, indicating an early response. Liver resection was performed in 4 patients (22.2%). The incidence of any adverse events (Grade 3/4) was 28% (5/18), including skin disorder (16.7%) as dry skin, cutaneous pruritus, contusion and paronychia, as well as peripheral sensory neuropathy (11.1%). The any-grade events of skin disorders and peripheral sensory neuropathy were mostly observed in all patients. These events were controllable by preventive skin care and by withdrawal and dose reduction, respectively. Death due to adverse events was not observed. Adverse events did not require the withdrawal of this regimen. Conclusion: Based on the 18 patients studied, combined therapy with SOX+cetuximab was free of serious adverse events and could be safely administered by reducing the dose or temporarily suspending treatment, as required. These regimens seem to be promising for conversion therapy (4 out of 18 patients) because of good outcomes and an early response.

Sunday, April 17, 2016 6:00 PM|Kirsten Bryant|Cancers|Labels: RAS, pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an “undruggable” protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient’s immune system to fight their cancer is an additional exciting route that is being considered. The “best” path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS.
Saturday, March 19, 2016 10:51 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, RAS, lung cancer
CONCLUSIONS: This is the largest three gene molecular epidemiology study in East Asian NSCLC patients. Each genetic alteration was associated with distinct clinicopathologic characteristics. Furthermore, different age and sex are associated with different subtypes of EGFR and KRAS mutations. PMID: 26992209 [PubMed - as supplied by publisher] (Source: Oncotarget)
Saturday, March 19, 2016 10:51 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, EGFR, RAS, lung cancer
CONCLUSION: Fifty eight percent of patients wild type by standard testing for EGFR/KRAS/ALK have GAs identifiable by CGP that suggest benefit from target therapy. CGP used when standard molecular testing for NSCLC is negative can reveal additional avenues of benefit from targeted therapy. PMID: 26992220 [PubMed - as supplied by publisher] (Source: Oncotarget)
Friday, March 18, 2016 5:00 PM|Annals of Oncology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS, lung cancer
Conclusions This study failed to show improvement in ORR or PFS with combination therapy of selumetinib and erlotinib over monotherapy in KRAS mutant and KRAS wild-type advanced NSCLC. The association of immune subsets and immune checkpoint receptor expression with selumetinib may warrant further studies. (Source: Annals of Oncology)
Friday, March 18, 2016 5:00 PM|Cancer Genetics and Cytogenetics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS, lung cancer
KRAS mutant non-small cell lung cancers (NSCLCs) vary in clinical outcome depending on which specific KRAS mutation is present. Shorter progression free survival has been associated with KRAS variants G12C and G12V. Cell lines with these variants depend to a greater extent upon the RAS/RAF/MEK/ERK signaling pathway and become more susceptible to MEK inhibition. Because different KRAS mutations may lead to altered drug sensitivity, we aimed to determine specific KRAS mutation status in a NSCLC patient cohort at our institution. (Source: Cancer Genetics and Cytogenetics)
CONCLUSIONSThe selective, single‐agent activity of trametinib against RAS‐mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
CONCLUSIONSThe coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high‐risk patients with DTC. Cancer 2016. © 2016 American Cancer Society. (Source: Cancer)
Thursday, March 10, 2016 1:22 PM|Recent Patents on Anti-Cancer Drug Discovery|MedWorm: Cancer Therapy|Comments|Labels: EGFR, RAS, HNN
Authors: Oliveira-Silva J, de Carvalho AC, de Souza Viana L, Carvalho AL, Reis RM Abstract Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that activates downstream signaling pathways, including the Ras-MEK-Erk and PI3K-AKT pathways, leading to cell proliferation, resistance to apoptosis, angiogenesis and the ability to metastasize. EGFR overexpression is a significant finding in cancer, particularly in head and neck cancer, where it is also associated with a poor prognosis. In recent years, several molecules have been designed to inhibit EGFR activation. Among the many available anti-EGFR drugs, only cetuximab was approved for the treatment of head and neck cancers. However, no predictive biomarkers of cetuximab response are currently known. In the present re...
Thursday, March 10, 2016 1:20 AM|oslocancer|investoropportunities – Oslo Cancer Cluster|Labels: RAS, pancreatic cancer

Oslo Cancer Cluster member Targovax has conducted a predetermined interim analysis of the TG01 Phase I/II trial, indicating promising 1-year overall survival data when combining TG01 with gemcitabine, chemotherapy, as supplementary treatment of patients with pancreatic cancer.

 

Of the 19 patients included in the study, 15 patients provided consent to be followed up for survival and four patients did not provide consent to be followed up. 1-year survival data showed that 14 out of these 15 patient were alive and one passed away due to pneumonia assessed by the investigator as unrelated to the patients underlying cancer.

The regimen was generally well tolerated and RAS specific T-cell immune responses were induced and enhanced when TG01/GM-CSF was administered in combination with gemcitabine (1).

“One must be careful when drawing conclusions from small survival trials, but this result is an encouraging signal of efficacy and we look forward to the two year survival data which is expected during the first half year of next year“, says Gunnar Gårdemyr, CEO of Targovax.

The study is a single arm study of TG01 in combination with standard of care gemcitabine as adjuvant treatment of patients with operable pancreatic cancer. The interim analysis covered 1-year survival of the first cohort of 19 patients.

References: 1-year overall survival in two independent studies of patients with resected adenocarcinoma of the pancreas receiving standard of care gemcitabine were both approximately 75% (2,3).

 

About Targovax: “Arming the patient’s immune system to fight cancer”

Targovax is a clinical stage immuno-oncology company developing targeted immunotherapy treatments for cancer patients. Targovax has a broad and diversified immune therapy portfolio and aims to become a leader in its area. The company is currently developing two complementary and highly targeted approaches to immuno-oncology:

ONCOS- 102 is part of a virus-based immunotherapy platform based on engineered oncolytic viruses armed with potent immune-stimulating transgenes targeting solid tumors. This treatment may reinstate the immune system’s capacity to recognize and attack cancer cells.

TG01 and TG02 are part of a peptide-based immunotherapy platform targeting the difficult to treat RAS mutations found in more than 85% of pancreatic cancers, 50% of colorectal cancers and 20-30% of all cancers. Targovax is working towards demonstrating that TG vaccines will prolong time to cancer progression and increase survival.

The product candidates will be developed in combination with multiple treatments in several cancer indications, including checkpoint inhibitors. Targovax also has a number of other cancer immune therapy candidates in early stage of development. For more information go to www.targovax.com

Monday, March 7, 2016 4:00 PM|Cancer Biology and Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, PD-1/PD-L1, RAS, lung cancer
This study was aimed to detect the correlation among EGFR/KRAS status and PD-1/PD-L1 expression in non-small-cell lung cancer (NSCLC) patients. PD-1 and PD-L1 expressions were detected by immunohistochemistry in 100 surgically resected lung adenocarcinoma tissues and were statistically correlated with clinicopathological characteristics including EGFR and KRAS statuses. Besides, the overall survival (OS) times were analyzed. There was a statistical significances between PD-1 expression in tumor and KRAS status (P = 0.043), with a higher mutation rate in with lower PD-1 expression patients. There was a statistical significance between PD-L1 expression in tumor and EGFR status (P = 0.012), with a higher mutation rate in patients with lower PD-L1 expression. The OS of patients with EGFR mutat...
Saturday, March 5, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Transitional Cell Carcinoma|Comments|Labels: RAS, bladder cancer
While pharmacoepidemiologic and laboratory studies have supported the hypothesis that the antidiabetic drug metformin may be useful in treating or preventing cancer, there is limited evidence to suggest which specific cancer sites may be particularly sensitive. Sensitivity likely is determined both by features of tumor pathophysiology and by pharmacokinetic factors. We used UPII-mutant Ha-ras transgenic mice that develop hyperplasia and low-grade, papillary urothelial cell carcinoma to determine whether metformin has activity in a model of superficial bladder cancer. Metformin significantly improved survival, reduced urinary tract obstruction, reduced bladder weight (a surrogate for tumor volume), and led to clear activation of AMP α kinase and inhibition of mTOR signaling in neoplas...
Monday, February 29, 2016 5:00 PM|Meluch, A.|The Oncologist Subject Collection: Gastrointestinal Cancer|Labels: RAS, CRC, clinical trial
Lessons LearnedO_LIThis regimen is a viable option for patients with liver-only metastatic colorectal cancer. C_LIO_LIEnrollment criteria for future studies should include testing for the newly identified KRAS mutations. C_LI Background.Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis. Methods.Patients received FOLFOXIRI (5-FU, 3,200 mg/m2, 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m2 i.v.; irinotecan, 125 mg/m2; oxaliplatin, 85 mg/m2 i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate. Results.Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found. Conclusion.KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.
Monday, February 29, 2016 4:00 PM|Pathology International|Pathology International via MedWorm.com|Comments|Labels: RAS, lung cancer
Tumors harboring osteoclast‐like giant cells (OGCs) at extraosseous site are extremely rare. These rare tumors have been detected most frequently in the pancreas and few pulmonary tumors harboring OGCs have been previously reported. In addition, the genetic profiles of these tumors have remained virtually unknown. Therefore, we report a case of pulmonary adenocarcinoma harboring OGCs in which k‐ras mutation and immunohistochemical study of proteins associated with OGCs were examined. The case was a 70‐year‐old man, who demonstrated a pulmonary mass associated with unusual radiological features. Histopathologically, three different cell types, mucinous adenocarcinoma cell, OGC and mononuclear cell were detected. OGCs were immunohistochemically negative for epithelial markers and pos...
Sunday, February 28, 2016 4:00 PM|European Respiratory Review|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS, lung cancer
KRAS mutations are the most frequent molecular abnormalities found in one out of four nonsmall cell lung cancers (NSCLC). Their incidence increases in cases of adenocarcinoma, smokers and Caucasian patients. Their negative value in terms of prognosis and responsiveness to both standard chemotherapy and targeted therapies remains under debate. Many drugs have been developed specifically for KRAS-mutated NSCLC patients. Direct inhibition of RAS activation failed to show any clinical efficacy. Inhibition of downstream targets of the mitogen-activated protein kinase (MEK) pathway is a promising strategy: phase II combinations of MEK 1/2 kinase inhibitors with chemotherapy doubled patients’ clinical outcomes. One phase III trial in such a setting is ongoing. Double inhibition of MEK and e...
Tuesday, February 23, 2016 4:00 PM|Clinical Colorectal Cancer|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS
Authors: Kou T, Kanai M, Matsumoto S, Okuno Y, Muto M Abstract Comprehensive genomic profiling using next-generation sequencing technologies provides insights into understanding the genomic architecture of human cancer. This new understanding of the cancer genome allows us to identify many more genomic alterations occurring within tumors than before, some of which could be potential therapeutic targets through molecular targeted agents. Currently, a large number of molecular targeted agents are being developed, and consequently, cancer treatment is rapidly shifting from empiric therapy employing cytotoxic anticancer drugs to genotype-directed therapy using molecular targeted agents. In current daily clinical practice, hotspot-based single-gene assays that detect RAS mutations in co...
Wednesday, February 17, 2016 4:00 PM|Cellular and Molecular Life Sciences : CMLS|MedWorm: Cancer Therapy|Comments|Labels: RAS
Authors: Zhang F, Cheong JK Abstract The RAS genes encode for members of a large superfamily of guanosine-5'-triphosphate (GTP)-binding proteins that control diverse intracellular signaling pathways to promote cell proliferation. Somatic mutations in the RAS oncogenes are the most common activating lesions found in human cancers. These mutations invariably result in the gain-of-function of RAS by impairing GTP hydrolysis and are frequently associated with poor responses to standard cancer therapies. In this review, we summarize key findings of past and present landmark studies that have deepened our understanding of the RAS biology in the context of oncogenesis. We also discuss how emerging areas of research could further bolster a renewed global effort to target the largely undrug...

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Thursday, February 4, 2016 4:00 PM|Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms|MedWorm: Cancer Therapy|Comments|Labels: RAS
We describe the nuclear proteins that recognize these unusual DNA structures and discuss their function in transcription. We also examine the formation of G-quadruplexes in the 5′-untranslated region of the ras transcripts and conclude this review by reporting strategies that use either ras G-quadruplexes or proteins recognizing the ras G-quadruplexes as targets of anticancer small molecules. (Source: Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms)
Tuesday, February 2, 2016 4:00 PM|Cancer Chemotherapy and Pharmacology|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: ALK, BRAF, EGFR, PI3K, RAS, ROS, lung cancer
Conclusion Combined analysis of these commonly studied genes may promote the individual treatment in NSCLC. RRM1 may be a prognostic and predictive biomarker for PFS in patients with NSCLC who received platinum-based adjuvant chemotherapy, and combining EGFR mutation and RRM1 expression or combining ERCC1 and RRM1 expression can enhance prognostic and predictive power for PFS. (Source: Cancer Chemotherapy and Pharmacology)
Monday, January 25, 2016 4:00 PM|Epidemiologic Perspectives and Innovations|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS, lung cancer
Conclusions: Cumulatively, these results signify a crucial role of the anti-inflammatory agent aspirin as a novel negative regulator of epithelial-to-mesenchymal transition thereby suggesting its candidature as a promising tool for deterring metastasis of highly invasive K-ras-expressing NSCLC cells. (Source: Epidemiologic Perspectives and Innovations)
Sunday, January 24, 2016 1:59 AM|Oncotarget|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: EGFR, RAS, lung cancer
CONCLUSIONS: MUTKRAS could be an additional mechanism of escape from EGFR-TKI inhibition and cftDNA is a feasible approach to monitor the molecular development of drug resistance. PMID: 26799287 [PubMed - as supplied by publisher] (Source: Oncotarget)
Saturday, January 23, 2016 12:38 AM|Advances in Bioinformatics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: RAS, lung cancer
Authors: Fatima A, Yee HF Abstract K-ras is an oncogenic GTPase responsible for at least 15-25% of all non-small cell lung cancer cases worldwide. Lung cancer of both types is increasing with an alarming rate due to smoking habits in Malaysia among men and women. Natural products always offer alternate treatment therapies that are safe and effective. Typhonium flagelliforme or Keladi Tikus is a local plant known to possess anticancer properties. The whole extract is considered more potent than individual constituents. Since K-ras is the key protein in lung cancer, our aim was to identify the constituents of the plant that could target the mutated K-ras. Using docking strategies, reported potentially active compounds of Typhonium flagelliforme were docked into the allosteric surface...

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Friday, January 22, 2016 2:15 PM|News-Medical.Net Cetuximab News Feed|Comments|Labels: BRAF, RAS, CRC
A post hoc analysis of the PETACC-8 trial has revealed an interaction between microsatellite instability and BRAF and KRAS mutation status when determining the prognosis of patients with resected stage III colon adenocarcinoma.
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: HSP, RAS, lung cancer
Conclusion: The dual inhibition of HSP90 and MEK signaling pathways on sub-effective dose may constitute a potent therapeutic strategy to treat intrinsic MEK inhibitor resistant G13DKRAS mutant NSCLCs for resolving toxicity problem of dual inhibition of AKT and MEK in clinical trials.Citation Format: Dae Ho Lee, Kang-Seo Park, Bora Oh, Mi-Hee Lee, Hannah Yang. HSP90 inhibitor NVP-AUY922 sensitizes intrinsic MEK inhibitor Trametinib-resistant NSCLC cells harboring KRAS mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B90. (Source: Molecular Cancer Therapeutics)
Wednesday, January 6, 2016 4:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: EGFR, RAS, breast cancer
Tumor microenvironment (TME) plays a critical role in tumor growth, invasion and metastasis. In TME, epidermal growth factor receptor (EGFR) family members, including HER1, HER2, HER3 and HER4, are involved in determining aggressive growth of breast cancer due to their ability to transduce the growth promoting functions of growth factors. This activity is potentiated by the over-expression of these receptor molecules in cancer cells. To reduce the activity of EGFR molecules, various inhibitors have been developed. EGFR/HER1 tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show antitumor activity but these drugs have not meet their primary goal of improved survival in the overall patient population. A similar TKI, lapatinib, has shown some limited success in breast cancer. While ...