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

Abstract

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. .

MiR‐205 suppresses tumor growth, invasion, and epithelial‐mesenchymal transition by targeting SEMA4C in hepatocellular carcinoma

“…Previous studies have demonstrated that SEMA4C promoted the proliferation and migration of cancer cells by activating PlexinB2-MET signaling. Interestingly, aberrant activation of Met signaling was confirmed to be closely associated with tumor growth, angiogenesis, metastasis, and poor survival in HCC (36,37). Furthermore, Met can also activate an EMT program in human HCC cells (38).…”

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

“…(23) This negative result could be explained by the fact that tivantinib was ultimately not a MET inhibitor and that MET overexpression at immunohistochemistry was not a reliable surrogate marker of oncogene addiction to the MET pathway. (24) As a proof of concept, we showed that whole-exome sequencing of HCC biopsy could reveal rare biomarkers predictive of treatment response to a specific inhibitor. MET amplification, a rare genetic alteration present in only 1% of HCC, was associated with complete response to the MET inhibitor MSC2156119J in our study.…”

“…However, a recent phase 3 randomized controlled trial comparing tivantinib, initially considered a MET inhibitor, versus placebo in advanced HCC with MET overexpression at immunohistochemistry failed to improve overall survival . This negative result could be explained by the fact that tivantinib was ultimately not a MET inhibitor and that MET overexpression at immunohistochemistry was not a reliable surrogate marker of oncogene addiction to the MET pathway …”

Dual Targeting of Histone Methyltransferase G9a and DNA‐Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma

“…The origin and culture of the 32 HCC cell lines used in this study has been previously described . The human hepatic stellate cell (hHSC) line LX2 (Millipore‐Merck, Darmstadt, Germany), was cultured in DMEM supplemented with 2% fetal bovine serum and antibiotics.…”

“…The origin and culture of the 32 HCC cell lines used in this study has been previously described. (23) The human hepatic stellate cell (hHSC) line LX2 (Millipore-Merck, Darmstadt, Germany), was cultured in DMEM supplemented with 2% fetal bovine serum and antibiotics. Primary hHSCs were isolated from resected liver wedges obtained from patients undergoing surgery at the Royal Free Hospital (London, United Kingdom) after giving informed consent (#EC01.14-RF).…”