Abstract C177: TAS-117, a highly selective non-ATP competitive inhibitor of AKT demonstrated antitumor activity in combination with chemotherapeutic agents and molecular targeted drugs.

Abstract

Abstract Background: TAS-117 is a potent and highly selective non-ATP competitive small molecule inhibitor of AKT. AKT controls cellular proliferation and resistance to apoptosis, and is known to be activated in patients with relapsed or refractory tumors. Thus the combination of TAS-117 and cytotoxic drugs could be a promising approach to treat cancers. In addition, recent preclinical and clinical studies suggest that the vertical inhibition of key cancer signaling pathways may be an effective way to minimize crosstalk signaling and compensatory feedback activation. Therefore, we evaluated these combination approaches using TAS-117. Materials and Methods: A PTEN negative human ovarian cancer cell line A2780 and HER2 overexpressing human gastric cancer cell lines NCI-N87 and 4-1ST were used. In vitro combination studies were conducted by using CellTiter Glo™ assays. For in vivo studies, cells were subcutaneously transplanted into the side flank of nude mice. TAS-117, S-1, lapatinib, and everolimus were given by daily oral dosing. Carboplatin and irinotecan were given by weekly i.v. bolus injection. Trastuzumab was given by weekly i.p. bolus injection. Tumor volumes and body weights were measured twice a week. Apoptosis induction and pathway inhibition were determined by immunoblotting. Results: The in vitro combination studies revealed that TAS-117 enhanced the cytotoxicity of cisplatin, SN38, and fluorouracil in A2780 cells. In vivo, TAS-117 significantly improved the antitumor effect of carboplatin or irinotecan in an A2780 xenograft model. TAS-117 also enhanced the antitumor effect of S-1 in a 4-1ST xenograft model. With downstream, mTOR inhibitor everolimus, TAS-117 exhibited synergistic growth inhibition in NCI-N87 cells. Interestingly, cleavage of PARP was induced by the combination of TAS-117 and everolimus but not by either single agent alone. Enhanced antitumor activity in combination with TAS-117 and everolimus was confirmed in the NCI-N87 xenograft model. With an upstream, HER2 inhibitor lapatinib, TAS-117 also exhibited synergistic growth inhibition in vitro and enhanced antitumor activity in vivo in the NCI-N87 model. The combinatorial effect of TAS-117 and HER2 blockade was further evaluated using trastuzumab. TAS-117 strongly enhanced the antitumor effect of trastuzumab in a 4-1ST xenograft model. Conclusion: TAS-117 was effective in combination with chemotherapeutic agents including paclitaxel, carboplatin, irinotecan and S-1. Vertical pathway inhibition by TAS-117 with trastuzumab, lapatinib and everolimus were also effective. Our studies provide a strong rationale for clinical evaluation of our highly selective AKT inhibitor TAS-117 in combination with chemotherapeutic agents and molecular targeted drugs. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C177. Citation Format: Koji Ichikawa, Tetsuya Abe, Hideki Nagase, Hitoshi Saito, Ryouto Fujita, Megumu Okada, Kazuhiko Yonekura, Toshiyasu Shimomura, Teruhiro Utsugi. TAS-117, a highly selective non-ATP competitive inhibitor of AKT demonstrated antitumor activity in combination with chemotherapeutic agents and molecular targeted drugs. [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 C177.