Tivantinib (ARQ197) Displays Cytotoxic Activity That Is Independent of Its Ability to Bind MET
2013
Purpose: MET, the high-affinity receptor for hepatocyte growth factor, is frequently deregulated in humancancer.Tivantinib(ARQ197;Arqule),astaurosporinederivativethatbindstothedephosphorylated METkinaseinvitro,isbeingtested clinicallyasahighlyselectiveMETinhibitor.However,themechanismof action of tivantinib is still unclear. ExperimentalDesign:Theactivityoftivantinibwasanalyzedinmultiplecellularmodels,including:cells displayingc-METgeneamplification,strictly‘addicted’toMETsignaling;cellswithnormalc-METgenecopy 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’byMETkinasehyperactivation,wherecellsdieunlessculturedinthepresenceofaspecific 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.
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