Proliferation Markers Are Associated with MET Expression in Hepatocellular Carcinoma and Predict Tivantinib Sensitivity In Vitro

• Published in: Clinical cancer research 2017-08, Vol.23 (15), p.4364-4375
• Main Authors: Rebouissou, Sandra, La Bella, Tiziana, Rekik, Samia, Imbeaud, Sandrine, Calatayud, Anna-Line, Rohr-Udilova, Nataliya, Martin, Yoann, Couchy, Gabrielle, Bioulac-Sage, Paulette, Grasl-Kraupp, Bettina, de Koning, Leanne, Ganne-Carrié, Nathalie, Nault, Jean-Charles, Ziol, Marianne, Zucman-Rossi, Jessica
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antitumor activity; Biomarkers; Biomarkers, Tumor - genetics; Biotechnology; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Clinical trials; Drug Resistance, Neoplasm - drug effects; Drugs; Experimental design; Gene amplification; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene sequencing; Genes; Hepatocellular carcinoma; Hepatocytes; Humans; Life Sciences; Liver; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical research; MET protein; Mitosis; Paclitaxel; Patients; Pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Pyrrolidinones - administration & dosage; Pyrrolidinones - adverse effects; Quinolines - administration & dosage; Quinolines - adverse effects; Sensitivity; Sensitivity analysis; Signaling; Tumor cell lines; Tumors; Vinblastine; Whole Exome Sequencing
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-3118

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. 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. 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 displaying gene 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. 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. .