Abstract A268: TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant cells.

Abstract

Abstract Background: Aurora A is a serine/ threonine kinase that plays a critical role in regulating multiple mitosis processes. Aberrant expression of Aurora A has been associated with spindle checkpoint dysfunction and increased resistance to the microtubule-polymerizing agents, paclitaxel and docetaxel (1). Aurora A has been identified as one of the genes associated with enhancement of paclitaxel cytotoxicity in a siRNA library screen (2). Moreover, Aurora A overexpression/ gene amplification has been reported in various types of human cancers. In this report, we demonstrate that a selective Aurora kinase A inhibitor, TAS-119, synergistically enhances the activity of paclitaxel in multiple cell lines in vitro. Materials and Methods: Evaluation of synergistic effects in combination was conducted by curve-shift analysis and Bliss additivity model, based on cell viability. Cell viability was assayed by using CellTiter-Glo™ which measures cellular ATP. Selectivity of TAS-119 for three isotypes of Aurora kinases was determined via monitoring the auto-phosphorylation of kinases by Western blot. Apoptosis induction was assessed by cleaved-PARP detection. As paclitaxel-resistant cell lines, both A549.T12 (3) and PTX10 (4) were used in combination experiments. A549.T12 and PTX10 were reported to have altered expression of β-tubulin isotypes and β-tubulin mutation, respectively. Results: TAS-119 selectively inhibited cellular auto-phosphorylation of Aurora A without affecting the activity of both Aurora B and Aurora C. TAS-119 showed a synergistic effect with paclitaxel or docetaxel in multiple tumor cell lines from different origins, even in cells insensitive to TAS-119 treatment alone. Furthermore, TAS-119 also showed synergistic effects in paclitaxel-resistant cell lines. Cleaved-PARP analysis revealed that the cytotoxic synergism in combination with paclitaxel was induced by promoting the caspase-dependent apoptotic cell death. Conclusion: The unique characteristic of TAS-119 as a highly selective Aurora A inhibitor contributed to the synergistic enhancement of antiproliferative effects of taxanes in multiple cell lines, possibly mediated by apoptotic pathways. These findings provide a rationale for the clinical development of TAS-119 as a combination therapy with taxanes. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A268. Citation Format: Akihiro Miura, Hiroshi Sootome, Keiko Ishihara, Norio Masuko, Hiroshi Hirai, Teruhiro Utsugi. TAS-119, a selective Aurora A inhibitor, enhanced the antitumor efficacy of taxanes in multiple human tumor cell lines including paclitaxel-resistant cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A268.