A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity

Background: Aurora A is a serine/threonine kinase that plays important roles in the regulation of the M phase of the mammalian cell cycle. Aberrant expression of Aurora A has been associated with spindle checkpoint dysfunction and increased resistance to the microtubule-polymerizing agents, paclitaxel and docetaxel (1). Moreover, Aurora A overexpression/ gene amplification has been reported in various types of human cancers. Previously, we have reported on the development of a highly potent and selective Aurora A inhibitor, TAS-119 (TAS-2104), which enhanced anti-proliferation activity by taxanes (2). This study was undertaken to select the optimal combination schedule of TAS-119 and taxanes both in vitro and in vivo. Additionally, we evaluated the effects of TAS-119 on peripheral neurotoxicity, a well known major toxicity of taxanes. Materials and Methods: For in vitro experiments, cells were exposed to paclitaxel and/or the Aurora A inhibitor in different order and duration. Cell viability was determined by measuring cellular ATP concentration. For an in vivo tumor efficacy study, human tumor cell lines were subcutaneously transplanted into the side flank of nude mice or rats. Dosing of taxanes and TAS-119 was started when the transplanted tumor size reached > ∼ 200 mm3. Peripheral neurotoxicity was evaluated in rats. Paclitaxel was dosed weekly for 8 weeks and neurotoxicity was assayed by changes of action potential (M-wave amplitude) after electrical stimuli or histopathology changes in nerve neurons. Results: In in vitro experiments, the Aurora A inhibitor enhanced paclitaxel activity in all 3 schedules tested; Aurora A inhibitor before or after paclitaxel or simultaneous treatment. However, the latter 2 schedules were better than first schedule. When different treatment duration times of the Aurora A inhibitor combined with a single dose of paclitaxel were tested, 48 hrs was found to be enough to cause maximum enhancement. Similar experiments were performed in in vivo xenograft models. Maximum enhancement by TAS-119 was observed with 2 to 4 days of treatment (dependent on the model). Moreover, the combination of TAS-119 did not exacerbate the paclitaxel-induced peripheral neurotoxicity in rats. Conclusion: In this study, intermittent dosing of TAS-119 is efficacious for combination with taxanes, and sustained exposure of TAS-119 is not required for maximal combination efficacy. These findings provide a rationale for the clinical evaluation of combination therapies of TAS-119 with taxanes under the defined optimal schedule. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A269. Citation Format: Keiko Ishihara, Hiroshi Sootome, Takamasa Suzuki, Norio Masuko, Akihiro Miura, Megumu Okada, Nobuyuki Oda, Hiroshi Hirai, Teruhiro Utsugi. A selective Aurora A inhibitor, TAS-119, enhanced the antitumor activity of taxanes in an intermittent dosing schedule without affecting neurotoxicity. [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 A269.