Proliferation markers are associated with MET expression in hepatocellular carcinoma and predict tivantinib sensitivity in vitro.

Rebouissou S, La Bella T, Rekik S et al.

UMR 1162, Université Paris Descartes – Paris Diderot – Paris 13.

Clinical cancer research : an official journal of the American Association for Cancer Research. Feb 2017.

Tivantinib was initially reported as a selective MET inhibitor and is under phase 3 evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has been also proposed as an antimitotic agent. We aimed to evaluate the anti-tumor effect of tivantinib in HCC cells by combining pharmacological 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 and mitotic index quantification. Expression of candidate biomarkers predicting drug response was analyzed in 310 HCC.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 placitaxel. In contrast, tivantinib did not suppress MET signaling and selective MET inhibitors demonstrated an anti-proliferative effect only in MHCC97H, the unique cell line displaying MET 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.


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