title: Tivantinib (ARQ197) displays cytotoxic activity that is independent of its ability to bind MET.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Laboratory of Experimental Therapy, Institute for Cancer Research and Treatment (IRCC), Candiolo, Turin, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Basilico
authors.forename: Selma
authors.initials: S
authors.lastname: Pennacchietti
authors.forename: Elisa
authors.initials: E
authors.lastname: Vigna
authors.forename: Cristina
authors.initials: C
authors.lastname: Chiriaco
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Donatella
authors.initials: D
authors.lastname: Valdembri
authors.forename: Guido
authors.initials: G
authors.lastname: Serini
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D018628:Gene Dosage; D056945:Hep G2 Cells; D006801:Humans; D008870:Microtubules / Q000187:drug effects; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: C551661:ARQ 197; D000970:Antineoplastic Agents; D011760:Pyrrolidinones; D011804:Quinolines; D050257:Tubulin Modulators; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met