Abstract B88: TAS-114, a dUTPase inhibitor, in combination with pemetrexed is a novel strategy for the treatment of NSCLC.

Abstract

Abstract Background: Deoxyuridine 5'-triphosphate nucleotidehydrolase (dUTPase) is a gatekeeper protein, which prevents uracil misincorporation into DNA in cancer cells. dUTPase may protect cancer cells from aberrant base mediated cytotoxicity during thymidylate synthase (TS) inhibition, and its overexpression is associated with resistance to TS inhibitors. TAS-114 is a novel orally available dUTPase inhibitor and Phase I studies with TS-targeted drugs (S-1 and Capecitabine) are ongoing. Pemetrexed is an antifolate-based TS inhibitor and has been proven efficacious for the treatment of non-squamous non-small cell lung cancer (NSCLC). Here, we evaluated the therapeutic possibility of TAS-114 in combination with pemetrexed in NSCLC models. Materials and Methods: In vitro cell growth inhibition was determined by Crystal Violet, using 14 human lung cancer cell lines. The antitumor activity of TAS-114/pemetrexed was also evaluated in NCI-H2228 (human NSCLC), MX-1 (human breast cancer) and Bu25 TK- (human cervical cancer, thymidine kinase deficient) xenograft mouse models for preclinical proof of concept. MX-1 is a dUTPase highly expressed tumor, and Bu25 TK- is a pemetrexed-sensitve model, due to the lack of thymidine salvage pathway within the tumor cells. Intratumoral dUTPase inhibition was evaluated by measuring the dUTPase enzymatic product dUMP by HPLC. Results: TAS-114 significantly increased the cytotoxicity of pemetrexed in various human NSCLC cell lines in vitro. In an NCI-H2228 xenograft model, pemetrexed alone did not show antitumor activity, but oral administration of TAS-114 significantly enhanced the antitumor activity of pemetrexed. In addition, TAS-114 decreased intratumor dUMP accumulation mediated by pemetrexed-induced TS inhibition. Furthermore, strong antitumor activity of TAS-114/pemetrexed and pharmacodynamic modulation of pemetrexed after administration of TAS-114 were observed in the highly dUTPase expressed tumor MX-1. These results suggested that TAS-114 increased the antitumor activity of pemetrexed by dUTPase inhibition and subsequent uracil misincorporation into DNA. Finally, TAS-114 also enhanced the antitumor activity of pemetrexed in the pemetrexed-sensitive Bu25 TK- xenograft model. Conclusion: TAS-114/pemetrexed combination may represent a novel therapeutic strategy in NSCLC and other solid tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B88. Citation Format: Wakako Yano, Sayaka Tsukioka, Tatsushi Yokogawa, Satoko Ito, Keiji Ishida, Keisuke Yamamura, Akio Fujioka, Masayoshi Fukuoka, Kenichi Matsuo, Kazuharu Noguchi, Teruhiro Utsugi. TAS-114, a dUTPase inhibitor, in combination with pemetrexed is a novel strategy for the treatment of NSCLC. [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 B88.