title: Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1.
abstract: Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of HCC. It was shown that c-MET overexpression predicts its efficacy. Therefore, a phase-3 trial of tivantinib has been initiated to recruit "c-MET-high" patients only. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target. By assessing the mechanisms underlying the anticancer properties of tivantinib we showed that this agent causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1 and Bcl-xl, and by increasing Cyclin B1 expression regardless of c-MET status. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since HGF enhanced the expression of Mcl-1 and Bcl-xl. In summary, we show that the activity of tivantinib is independent of c-MET and describe Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that the predictive effect of c-MET expression in part reflects the c-MET-driven overexpression of Mcl-1 and Bcl-xl in c-MET-high patients and that these molecules are considered as possible response predictors.
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Helga-Paula
authors.initials: HP
authors.lastname: Török
authors.affiliation: Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Gallmeier
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.|Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, Berlin, Germany.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Kolligs
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzani
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Torino, Italy.|Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
authors.affiliation: Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany.
authors.forename: Enrico N
authors.initials: EN
authors.lastname: De Toni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D056744:Cyclin B1 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C551661:ARQ 197; C494811:BCL2L1 protein, human; C534699:CCNB1 protein, human; D056744:Cyclin B1; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; D051020:bcl-X Protein; D019859:Proto-Oncogene Proteins c-met
keywords: HCC; apoptosis; c-MET; targeted therapies