Cytotoxic Activity of Tivantinib (ARQ 197) Is Not Due Solely to c-MET Inhibition

摘要: The receptor tyrosine kinase c-MET is the high-affinity for hepatocyte growth factor (HGF). HGF/c-MET axis often dysregulated in tumors. activation can be caused by MET gene amplification, activating mutations, and auto- or paracrine mechanisms. Thus, inhibitors are under development as anticancer drugs. Tivantinib (ARQ 197) was reported a small-molecule inhibitor early clinical studies suggest antitumor activity. To assess whether activity of tivantinib due to inhibition c-MET, we compared with other both c-MET-addicted nonaddicted cancer cells. As expected, inhibitors, crizotinib PHA-665752, suppressed cancers, but not cancers that addicted c-MET. In contrast, inhibited cell viability similar potency These results exhibits its manner independent status. treatment induced G(2)-M cell-cycle arrest EBC1 cells similarly vincristine treatment, whereas PHA-665752 markedly G(0)-G(1) arrest. identify additional molecular target tivantinib, conducted COMPARE analysis, an silico screening database drug sensitivities across 39 lines (JFCR39), identified microtubule tivantinib. Tivantinib-treated showed typical disruption assembly vitro. inhibits polymerization addition inhibiting