title: Proliferation Markers Are Associated with MET Expression in Hepatocellular Carcinoma and Predict Tivantinib SensitivityIn Vitro.
abstract: Purpose:Tivantinib was initially reported as a selective MET inhibitor and is under phase III evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has been also proposed as an antimitotic agent. We aimed to evaluate the antitumor effect of tivantinib in HCC cells by combining pharmacologic and molecular profiling.Experimental Design:Sensitivity to tivantinib, JNJ-38877605, PHA-665752, vinblastine, and paclitaxel was tested in a panel of 35 liver cancer cell lines analyzed with exome sequencing, mRNA expression of 188 genes, and protein expression. Drug effect was investigated by Western blot analysis and mitotic index quantification. Expression of candidate biomarkers predicting drug response was analyzed in 310 HCCs.Results:Tivantinib sensitivity profiles in the 35 cell lines were similar to those obtained with antimitotic drugs. It induced blockage of cell mitosis, and high cell proliferation was associated with sensitivity to tivantinib, vinblastine, and paclitaxel. In contrast, tivantinib did not suppress MET signaling, and selective MET inhibitors demonstrated an antiproliferative effect only in MHCC97H, the unique cell line displayingMETgene amplification. HCC tumors with high expression of cell proliferation genes defined a group of patients with poor survival. Interestingly, highly proliferative tumors also demonstrated high MET expression, likely explaining better therapeutic response of MET-high HCC patients to tivantinib.Conclusions:Tivantinib acts as an antimitotic compound, and cell proliferation markers are the best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested in clinical trials to predict tivantinib response.Clin Cancer Res; 23(15); 4364-75. ©2017 AACR.
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Tiziana
authors.initials: T
authors.lastname: La Bella
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Rekik
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Anna-Line
authors.initials: AL
authors.lastname: Calatayud
authors.affiliation: Division of Gastroenterology and Hepatology, Clinic of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Rohr-Udilova
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Martin
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.affiliation: Bariton INSERM, UMR- 1053, Bordeaux, France.|Department of Pathology, Hôpital Pellegrin, CHU de Bordeaux, Bordeaux, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.affiliation: RPPA platform, Institut Curie, PSL Research University, Paris, France.
authors.forename: Leanne
authors.initials: L
authors.lastname: de Koning
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.|Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne-Carrié
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.|Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.|Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Nault
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France.|Liver Unit, Hôpital Jean Verdier, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Ziol
authors.affiliation: Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, Paris, France. jessica.zucman-rossi@inserm.fr.|Hôpital Europeen Georges Pompidou, F-75015, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects; D000073359:Exome Sequencing
chemical_list: C551661:ARQ 197; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011760:Pyrrolidinones; D011804:Quinolines; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met