Abstract 1642: Preclinical studies of MK-8745: Correlation between Aurora-A inhibitor sensitivity and Aurora-A activator

Abstract

Abstract Selective small-molecule kinase inhibitors have emerged as an important class of anti-cancer agents, and have demonstrated encouraging clinical efficacy in several different malignancies. However, it has become clear that the clinical activity of these agents is typically limited to a subset of patients, indicating the need to develop a clear understanding of the various factors that influence clinical benefit. To date, most studies have identified cancer patients whose tumors have genetic alterations of the targeted kinase and have demonstrated their greatest clinical efficacy for the kinase inhibitors. However, recent drug discovery efforts are also being aimed at targeting kinases within oncogene-associated signaling pathways and the pathway-specific determinants of sensitivity. Aurora-kinase family members (Aurora kinases -A, B, C) have been implicated as key mitotic regulators essential for genomic stability. Aurora kinase A (AURKA) is highly expressed in multiple human cancers and has been shown to be a promising therapeutic target. In this study, we examined the effects of small molecule AURKA specific inhibitor MK-8745 on non-Hodgkin lymphoma (NHL) cells. Our results indicate that MK-8745 treatment leads to cell cycle arrest at G2/M phase with accumulation of tetraploid DNA followed by mitotic catastrophe and cell death in five cell lines (Granta 519, Jeko1, JVM2, Z138C and Akata). More importantly, we found that the sensitivity of the cell to the AURKA inhibitor is strongly correlated to the expression level of AURKA activators. We found that siRNA knockdown of one of the AURKA activators TPX2 increased MK-8745 sensitivity in drug resistant cell lines (Granta 519), whereas overexpression of TPX2 in MK-8745 sensitive cell (Z138C) lines increased drug resistance. This differential drug-sensitivity is specific to MK-8745 since treatment with pan-Aurora inhibitor (VE465, inhibitor of Aurora-A, B and C) and another mitotic drug, Taxol, did not show a differential sensitivity in these cell lines. The AURKA phosphorylation was decreased by MK-8745 treatment with simultaneous reduction in endogenous AURKA substrate TPX2, Eg5 and TACC3 protein levels. Our results suggest, beside p53, AURKA activators should be potential biomarkers for selecting subpopulations of patients for AURKA inhibitor treatment, while AURKA substrates can be the potential biomarkers for the effect of Aurora-A inhibitor treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1642.