<p>PDF file - 800K, c-Met dependency of the used cell lines (S1); Antitumor activity of tivantinib on c-Met-non-addicted tumor cells (S2); Change in c-Met signaling after exposure to Tivantinib or Crizotinib for 24h (S3); Tivantinib did not inhibit c-MET activation in A549 cells (S4); Apoptosis induction by Tivantinib long time treatment in EBC-1 and MKN45 cells (S5); Tivantinib induces G2/M arrest as similar as tubulin inhibitor vincristine (S6); Growth inhibition against a panel of 39 human cancer cell lines by vincristine (S7); Tivantinib treatment led to a loss of microtubules in EBC1 cells (S8); Tivantinib short time treatment led to a loss of microtubules in A549 and EBC-1 cells (S9); Tivantinib inhibits tubulin polymerization in a dose dependent manner (S10).</p>
ARTICLE 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. c-MET activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, c-MET inhibitors are under development as anticancer drugs. Tivantinib (ARQ 197) was reported as a small-molecule c-MET inhibitor and early clinical studies suggest antitumor activity. To assess whether the antitumor activity of tivantinib was due to inhibition of c-MET, we compared the activity of tivantinib with other c-MET inhibitors in both c-MET–addicted and nonaddicted cancer cells. As expected, other c-MET inhibitors, crizotinib and PHA-665752, suppressed the growth of c-MET-addicted cancers, but not the growth of cancers that are not addicted to c-MET. In contrast, tivantinib inhibited cell viability with similar potency in both c-MET-addicted and nonaddicted cells. These results suggest that tivantinib exhibits its antitumor activity in a manner independent of c-MET status. Tivantinib treatment induced a G2–M cell-cycle arrest in EBC1 cells similarly to vincristine treatment, whereas PHA-665752 or crizotinib treatment markedly induced G0–G1 cell-cycle arrest. To identify the additional molecular target of tivantinib, we conducted COMPARE analysis, an in silico screening of a database of drug sensitivities across 39 cancer cell lines (JFCR39), and identified microtubule as a target of tivantinib. Tivantinib-treated cells showed typical microtubule disruption similar to vincristine and inhibited microtubule assembly in vitro. These results suggest that tivantinib inhibits microtubule polymerization in addition to inhibiting c-MET. Cancer Res; 73(10); 3087–96. ©2013 AACR.
