Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET
- 30 April 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (9), 2381-2392
- https://doi.org/10.1158/1078-0432.ccr-12-3459
Abstract
Purpose: MET, the high-affinity receptor for hepatocyte growth factor, is frequently deregulated in human cancer. Tivantinib (ARQ197; Arqule), a staurosporine derivative that binds to the dephosphorylated MET kinase in vitro, is being tested clinically as a highly selective MET inhibitor. However, the mechanism of action of tivantinib is still unclear. Experimental Design: The activity of tivantinib was analyzed in multiple cellular models, including: cells displaying c-MET gene amplification, strictly ‘addicted’ to MET signaling; cells with normal c-MET gene copy number, not dependent on MET for growth; cells not expressing MET; somatic knockout cells in which the ATP-binding cleft of MET, where tivantinib binds, was deleted by homologous recombination; and a cell system ‘poisoned’ by MET kinase hyperactivation, where cells die unless cultured in the presence of a specific MET inhibitor. Results: Tivantinib displayed cytotoxic activity independently of c-MET gene copy number and regardless of the presence or absence of MET. In both wild-type and isogenic knockout cells, tivantinib perturbed microtubule dynamics, induced G2/M arrest, and promoted apoptosis. Tivantinib did not rescue survival of cells ‘poisoned’ by MET kinase hyperactivation, but further incremented cell death. In all cell models analyzed, tivantinib did not inhibit HGF-dependent or -independent MET tyrosine autophosphorylation. Conclusions: We conclude that tivantinib displays cytotoxic activity via molecular mechanisms that are independent from its ability to bind MET. This notion has a relevant impact on the interpretation of clinical results, on the design of future clinical trials, and on the selection of patients receiving tivantinib treatment. Clin Cancer Res; 19(9); 2381–92. ©2013 AACR.Keywords
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