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Proliferation markers are associated with MET expression in hepatocellular carcinoma and predict tivantinib sensitivity in vitro
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Edité par CCSD ; American Association for Cancer Research -
International audience. Purpose: Tivantinib was initially reported as a selective MET inhibitor and is under phase 3evaluation in "MET-high" hepatocellular carcinoma (HCC) patients. However, it has beenalso proposed as an antimitotic agent. We aimed to evaluate the anti-tumor effect of tivantinibin HCC cells by combining pharmacological and molecular profiling.Experimental design: Sensitivity to tivantinib, JNJ-38877605, PHA-665752, vinblastine andpaclitaxel 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 bywestern blot and mitotic index quantification. Expression of candidate biomarkers predictingdrug response was analyzed in 310 HCC.Results: Tivantinib sensitivity profiles in the 35 cell lines were similar to those obtained withantimitotic drugs. It induced blockage of cell mitosis and high cell proliferation wasassociated with sensitivity to tivantinib, vinblastine and placitaxel. In contrast, tivantinib didnot suppress MET signaling and selective MET inhibitors demonstrated an anti-proliferativeeffect only in MHCC97H, the unique cell line displaying MET gene amplification. HCCtumors with high expression of cell proliferation genes defined a group of patients with poorsurvival. Interestingly, highly proliferative tumors also demonstrated high MET expressionlikely explaining better therapeutic response of MET-high HCC patients to tivantinib.Conclusions: Tivantinib acts as an antimitotic compound and cell proliferation markers arethe best predictors of its antitumor efficacy in cell lines. Ki67 expression should be tested inclinical trials to predict tivantinib response.
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