Oncology Intelligence

Aurora kinase
Aurora kinases are centromere associated serine/threonine kinases essential for mitosis, controlling chromatid segregation, and cell proliferation.(1, 2) Human Aurora kinases have an N-terminal domain, a protein kinase domain, and a short C-terminal domain. The N-terminal domain of three proteins share low sequence conservation, which determines selectivity during protein-protein interactions.(1, 3) Three Aurora kinases have been identified in mammalian cells to date: Auroras A and B are expressed in many different cell types, whereas the expression of aurora C seems to be restricted to testicular tissue.(5, 6)
Defects in chromatid segregation can cause genetic instability, a condition which is highly associated with the formation of tumors.(1, 2) The gene encoding the Aurora-A protein kinase is located in the 20q13 BC amplicon and is also overexpressed in CRC, pancreatic, and gastric tumors.(7) The mitotic/tubulin machinery is a validated drug target, exemplified by the success of the taxanes and vinca alkaloids. Aurora kinase inhibitors potentially have a benefit over these agents, because they target only those cells that enter mitosis, possibly improving specificity for dividing cells.(5) However, treatment with aurora kinase inhibitors in patients with solid tumors has been disappointing.(5,8) It is possible that inhibition of Aurora-A may not be sufficient for killing Aurora cancer cells. Chromosome instabilities observed in those mammary tumors support the hypothesis that activation or inactivation of effector proteins due to the gross alteration of chromosome structure may result in accelerating the formation of tumors. Simultaneous inhibition of this pathway as well as Aurora-A might be necessary for the better treatment of patients. mTOR/Akt pathway might be the one which is crucial for Aurora-A the formation of tumors.(9)



1. Hayflick L. Mortality and immortality at the cellular level. A review. Biochemistry-New York-English Translation of Biokhimiya. 1997;62(11):1180-90.

2. VM B-G. Aurora kinases. The International Journal of Biochemistry & Cell Biology. 2005;37:1572-7.

3. Bolanos-Garcia VM. Aurora kinases. The International Journal of Biochemistry & Cell Biology. 2005;37(8):1572-7.

4. PC GR. Aurora/Ipl1p-related kinases, a new oncogenic family of mitotic serine-threonine kinases. Journal of Cell Science. 1999;112:3591-601.

5. Boss DS BJ SJ. Clinical experience with aurora kinase inhibitors: a review. . Oncologist. 2009;14(8):780-93. PMCID: 19684075.

6. Kimura M MY YT, et. al. Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem. 1999;274:7334-40.

7. GF BA. Aurora-A: the maker and breaker of spindle poles. J Cell Sci. 2007;120((Pt 17)):2987-96. PMCID: 17715155.

8. Macurek L, Lindqvist A, Medema RH. Aurora-A and hBora join the game of Polo. CANCER RESEARCH. 2009;69(11):4555-8.

9. Saeki T, Ouchi M, Ouchi T. Physiological and oncogenic Aurora-A pathway. International journal of biological sciences. 2009;5(7):758.


4:06 PM|Current Cancer Drug Targets (Volume 16 - Issue 8)|Labels: aurora
Epigenetic modifications determine phenotypic characteristics in a reversible, stable and genotype-independent manner. Epigenetic modifications mainly encompass CpG island methylation and histone modifications, both being important in the pathogenesis of malignancies. The reversibility of epigenetic phenomenon provides a suitable therapeutic option that is reactivation of epigenetically silenced tumor-suppressor genes. Inhibition of DNA methyltransferase, histone deacetylase and Aurora B kinase, individually or collectively, could feasibly prevent or reverse the impact of epigenetic silencing. MicroRNAs [miRNAs] are an important layer of epigenetic controlling of gene expression, and serve as diagnostic and prognostic biomarkers as well as treatment targets for several types of cancer. miRNAs are involved inepigenetically silencing or activation of genes, tumor suppressor genes and oncogenes, and their modulation opens new horizons for designing novel cancer therapeutic agents.
6:46 AM|ZHELEV, Z., IVANOVA, D., BAKALOVA, R., AOKI, I., HIGASHI, T.|Anticancer Research current issue|Labels: aurora, leukemia

The aim of the present study was to investigate: (i) the possibility of sensitizing leukemia lymphocytes to anticancer drugs by inhibiting pentose-phosphate pathway using 6-aminonicotinamide (6-ANA); (ii) to find combinations with synergistic cytotoxic effect on leukemia lymphocytes and to investigate their cytotoxicity towards normal lymphocytes; (iii) and to clarify the role of reactive oxygen species (ROS) in the induction of apoptosis by those combinations. The study covers 15 anticancer drugs – conventional and new-generation. The experiments were performed on Jurkat leukemia cell line and normal lymphocytes, isolated from clinically healthy blood donors. Four parameters were analyzed simultaneously in both cell suspensions treated by drug or 6-ANA (separately, and in combination): cell viability, induction of apoptosis, level of ROS, and level of protein–carbonyl products. Most combinations of drug plus 6-ANA were characterized by synergistic cytotoxic effects on Jurkat cells. The synergism increased with increasing incubation time. Upon combination of 6-ANA with conventional chemotherapeutic (e.g. doxorubicin), synergistic cytotoxic effects were also detected in normal lymphocytes. In both cell types, the cytotoxicity of the combination of doxorubicin plus 6-ANA was accompanied by increased induction of apoptosis, but by a slight reduction of ROS and protein–carbonyl products compared to cells treated with doxorubicin only. Upon combination of 6-ANA with new-generation anticancer drugs (e.g. everolimus or barasertib), the synergistic cytotoxic effect on leukemia lymphocytes was also accompanied by very strong induction of apoptosis through ROS-independent mechanism(s). Neither of these combinations exhibited any cytotoxicity towards normal lymphocytes. The data suggest that 6-ANA could be used as a supplementary component in anticancer chemotherapy, and would allows therapeutic doses of anticancer drugs to be reduced, thereby minimizing their side-effects.

Wednesday, October 12, 2016 3:23 PM|Toshiaki SAEKI, Mutsuko OUCHI, Toru OUCHI|International Journal of Biological Sciences|Labels: aurora

Aurora family of protein kinases have emerged as crucial factors of, not only mitosis and cytokinesis, but also human carcinogenesis. Among these family members is Aurora-A that is frequently overexpressed in varieties of human cancer. Both in vitro and in vivo studies demonstrated that Aurora-A induces tumorigenesis through genome instability. These studies have further shown that cell signaling cross-talk between Aurora-A and other cellular proteins are essential for fully-transformed phenotypes. This review summarizes recent progress of Aurora-A-associated carcinogenesis.

Sunday, October 9, 2016 8:00 PM|Etienne Dardenne, Himisha Beltran, Matteo Benelli, Kaitlyn Gayvert, Adeline Berger, Loredana Puca, Joanna Cyrta, Andrea Sboner, Zohal Noorzad, Theresa MacDonald, Cynthia Cheung, Ka Shing Yuen, Dong Gao, Yu Chen, Martin Eilers, Juan-Miguel Mosquera, Brian D. Robinson, Olivier Elemento, Mark A. Rubin, Francesca Demichelis, David S. Rickman|Cancer Cell|Labels: aurora, prostate cancer
Dardenne et al. demonstrate that N-Myc overexpression in pre-clinical models drives aggressive prostate cancer that mimics human neuroendocrine prostate cancer, including reduced AR signaling and enhanced PRC2 target gene repression, and sensitizes cells to an Aurora-A inhibitor and EZH2 SET domain inhibitors.
Monday, October 3, 2016 12:05 AM|Sini, P., Gürtler, U., Zahn, S. K., Baumann, C., Rudolph, D., Baumgartinger, R., Strauss, E., Haslinger, C., Tontsch-Grunt, U., Waizenegger, I. C., Solca, F., Bader, G., Zoephel, A., Treu, M., Reiser, U., Garin-Chesa, P., Boehmelt, G., Kraut, N., Quant, J., Adolf, G. R.|Molecular Cancer Therapeutics current issue|Labels: aurora, MEK, skin cancer, biomarker diagnostic, clinical trial

Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388–98. ©2016 AACR.

Monday, October 3, 2016 12:05 AM|Helfrich, B. A., Kim, J., Gao, D., Chan, D. C., Zhang, Z., Tan, A.-C., Bunn, P. A.|Molecular Cancer Therapeutics current issue|Labels: aurora, lung cancer

Small-cell lung cancer (SCLC) cells have rapid proliferation, universal Rb inactivation, and high rates of MYC family amplification, making aurora kinase inhibition a natural target. Preclinical studies have demonstrated activity for Aurora A and pan-Aurora inhibitors with some relationship to MYC family expression. A clinical trial showed activity for an Aurora kinase A inhibitor, but no biomarkers were evaluated. We screened a panel of 23 SCLC lines with and without MYC family gene amplification or high MYC family gene expression for growth inhibition by the highly potent, selective aurora kinase B inhibitor barasertib. Nine of the SCLC lines were very sensitive to growth inhibition by barasertib, with IC50 values of <50 nmol/L and >75% growth inhibition at 100 nmol/L. Growth inhibition correlated with cMYC amplification (P = 0.018) and cMYC gene expression (P = 0.026). Sensitive cell lines were also enriched in a published MYC gene signature (P = 0.042). In vivo, barasertib inhibited the growth of xenografts established from an SCLC line that had high cMYC gene expression, no cMYC amplification, and was positive for the core MYC gene signature. Our studies suggest that SCLC tumors with cMYC amplification/high gene expression will frequently respond to Aurora B inhibitors and that clinical studies coupled with predictive biomarkers are indicated. Mol Cancer Ther; 15(10); 2314–22. ©2016 AACR.

Monday, August 15, 2016 12:05 AM|Ice, R., Kiseleva, A., Loskutov, Y., Smolkin, M., Salkeni, A., Hazard, H., Layne, G., Pugacheva, E.|Clinical Cancer Research recent issues|Labels: aurora, biomarker diagnostic

Background: Although advances in treating early stage breast cancers have increased the overall survival rate, once the disease has metastasized treatment options subside to palliative care. The limited access to metastatic biopsies and disease-relevant pre-clinical models to test new therapeutics targeted against advanced metastatic cancers limits progress and translation of investigational therapeutics to the clinic.

Methods: To address this deficiency we developed a collection of metastatic patient derived xenograft models via direct transplantation of metastatic biopsy or residual surgical material in immunocompromised mice. We successfully collected and established triple negative as well as ER/PR positive patient xenografts which are available for collaborative research. We further characterized and utilized the PDXs to assess the efficacy of new combination therapy to treat distant metastases.

Results: The efficacy of Aurora A kinase inhibition by small molecule inhibitor MLN8237 (Alisertib) as monotherapy and in combination with microtubule targeting drug, eribulin, on different stages of metastasis and potential mechanisms of its action was defined. Our work using PDX models indicates that Alisertib does not limit growth of the primary tumor. These findings are similar to the results of clinical trials with Alisertib in breast cancer. Importantly, we found that Alisertib dramatically decreases growth of the established metastases and prevents further dissemination via inactivation of AKT and activation of cytotoxic autophagy. Combination of Alisertib with eribulin led to a synergistic decrease in metastases to distant organs and provided additional local control of mammary tumor growth.

Conclusion: Metastatic PDX models provide new, accurate assessment of anti-metastatic regiment's efficacy. MLN8237 plus eribulin combination shows synergistic inhibition of metastatic spread, growth of established metastases and prolongs overall survival. Future clinical trials are needed to further test this regiment in clinic to improve survival of metastatic cancer patients.

Citation Format: Ryan Ice, Anna Kiseleva, Yuriy Loskutov, Matthew Smolkin, Adham Salkeni, Hannah Hazard, Ginger Layne, Elena Pugacheva{Authors}. Development of metastatic patient-derived xenografts (PDXs) for accurate assessment of anti-metastatic therapeutics in pre-clinical settings. [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 B20.

Tuesday, May 17, 2016 5:00 PM|Cancer|Cancer via|Comments|Labels: aurora, clinical trial
CONCLUSIONSAlisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m2 on day 1 in a 21‐day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524–33. © 2016 American Cancer Society. (Source: Cancer)
Wednesday, May 11, 2016 5:00 PM|Current Pharmaceutical Design|Current Pharmaceutical Design via|Comments|Labels: aurora, PLK, sarcoma
Authors: Cheng L, Wang C, Jing J Abstract Osteosarcoma is the most common type of pri¬mary bone tumor in adolescents and young adults. The dysregulation of cell cycle control and cell division often results in the aberrant growth of osteosarcoma cells. The primary proteins involved in cell cycle control and cell division include checkpoint kinases (CHKs), cyclin-dependent kinases (CDKs), polo-like kinases (PLKs) and aurora kinases (AURKs). In recent years, a large number of these protein kinase inhibitors have been identified in osteosarcoma. In this review, we highlight the current drugs being developed to target these protein kinases in osteosarcoma. PMID: 27174724 [PubMed - as supplied by publisher] (Source: Current Pharmaceutical Design)
Friday, May 6, 2016 5:00 PM|Bioorganic and Medicinal Chemistry Letters|Bioorganic and Medicinal Chemistry Letters via|Comments|Labels: aurora
Authors: An Y, Lee E, Yu Y, Yun J, Lee MY, Kang JS, Kim WY, Jeon R Abstract A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure-activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-depe...
Thursday, March 17, 2016 6:00 PM|Biochemical and Biophysical Research communications|MedWorm: Cancer Therapy|Comments|Labels: aurora, thymic
Authors: Maimaiti Y, Jie T, Jing Z, Changwen W, Pan Y, Chen C, Tao H Abstract Aurora-A (Aur-A), a member of the serine/threonine Aurora kinase family, plays an important role in ensuring genetic stability during cell division. Previous studies indicated that Aur-A possesses oncogenic activity and may be a valuable therapeutic target in cancer therapy. However, the role of Aur-A in the most common thyroid cancer, papillary thyroid cancer (PTC), remains largely unknown. In patients with PTC, cancer cell migration and invasion account for most of the metastasis, recurrence, and cancer-related deaths. Cofilin-1 (CFL-1) is the most important effector of actin polymerization and depolymerization, determining the direction of cell migration. Here, we assessed the correlation between Aur-A...
Friday, February 19, 2016 7:16 AM|Oncotarget|MedWorm: Cancer Therapy|Comments|Labels: aurora, sarcoma
Authors: Nair JS, Schwartz GK Abstract Aurora kinases have become an attractive target in cancer therapy due to their deregulated expression in human tumors. Liposarcoma, a type of soft tissue sarcoma in adults, account for approximately 20% of all adult soft tissue sarcomas. There are no effective chemotherapies for majority of these tumors. Efforts made to define the molecular basis of liposarcomas lead to the finding that besides the amplifications of CDK4 and MDM2, Aurora Kinase A, also was shown to be overexpressed. Based on these as well as mathematic modeling, we have carried out a successful preclinical study using CDK4 and IGF1R inhibitors in liposarcoma. MLN8237 has been shown to be a potent and selective inhibitor of Aurora A. MLN-8237, as per our results, induces a diff...
Saturday, February 6, 2016 6:00 PM|Molecular Cancer Therapeutics|MedWorm: Cancer Therapy|Comments|Labels: aurora, PLK, lung cancer
To overcome hurdles in identifying key kinases in small cell lung cancer (SCLC), we integrated a target-agnostic phenotypic screen of kinase inhibitors with target identification using activity-based protein profiling (ABPP) in which a desthiobiotin-ATP probe was used. We screened 21 SCLC cell lines with known c-MYC amplification status for alterations in viability using a chemical library of 235 small-molecule kinase inhibitors. One screen hit compound was interrogated with ABPP, and, through this approach, we reidentified Aurora kinase B as a critical kinase in MYC-amplified SCLC cells. We next extended the platform to a second compound that had activity in SCLC cell lines lacking c-MYC amplification and identified TANK-binding kinase 1, a kinase that affects cell viability, polo-like ki...