Abstract 4348: Antitumor activity of Tivantinib (ARQ 197) is due to inhibition of tubulin polymerization in addition to c-Met inhibition.

Abstract

Abstract The receptor tyrosine kinase c-Met is the high-affinity receptor for the hepatocyte growth factor (HGF). The HGF/c-Met axis is often dysregulated in tumors. Such c-Met activation is caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-Met inhibitors are under development as anti-cancer drugs. Tivantinib (ARQ 197) was reported as a small molecule Met inhibitor and early clinical studies suggest anti-tumor activity. To assess if the anti-tumor activity of tivantinib was due to inhibition of c-Met, we investigated the activity of tivantinib in both c-Met addicted and non-addicted cancer cells for cell viability. As expected, we observed that other Met inhibitors, crizotinib and PHA-665752, suppressed the growth of c-Met addicted cancers, but not the growth of c-Met non-addicted cells. In contrast, tivantinib inhibited cell viability similarly in both c-Met addicted and non-addicted cells. These results suggest that tivantinib exhibits its antitumor activity in a c-Met status independent manner. Tivantinib treatment increased the number of G2/M phase arrested EBC1 cells similarly as vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced cell cycle arrest at the G0/G1 phase. To identify the additional molecular target of tivantinib, we performed COMPARE analysis, in silico screening using extensive drug sensitivity database of 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib treated cells demonstrated typical microtubule disruption similar to vincristine. In vitro microtubule polymerization assay clearly demonstrated that tivantinib inhibited microtubule assembly. From these results, tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. Citation Format: Ryohei Katayama, Aki Aoyama, Takao Yamori, Jie Qi, Tomoko Ohara, Youngchul Song, Jeffrey A. Engelman, Naoya Fujita. Antitumor activity of Tivantinib (ARQ 197) is due to inhibition of tubulin polymerization in addition to c-Met inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4348. doi:10.1158/1538-7445.AM2013-4348