Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of hepatocellular carcinoma (HCC). It was shown that c-MET overexpression predicts its efficacy. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target.
Tivantinib is a highly selective c-Met tyrosine kinase inhibitor with a Ki of 355 nM.
In vitro: Tivantinib (ARQ 197) selectively inhibits c-Met activity in cell-free and cell-based assays. It inhibits constitutive and HGF-induced c-Met phosphorylation in various cancer cell lines. Meanwhile, the calculated inhibitory constant (Ki) of tivantinib for c-Met is approximately 355 nM.
In vivo: Tivantinib inhibits c-Met autophosphorylation in human colon xenograft tumors.Tumor xenografts are exposed to sustained plasma levels of tivantinib after oral administration.
In mechanism: Firstly, Tivantinib causes a strong loss of cell viability and of colony forming capability in a wide panel of cell lines from gastrointestinal tumors. Secondly, Tivantinib enhances apoptosis by inhibiting the mitochondrial regulators of apoptosis Mcl-1 and Bcl-xl. Meanwhile, Tivantinib-mediated accumulation of Cyclin B1 is associated with a G2/M cell cycle arrest. Moreover, the antiproliferative effect of tivantinib is independent of c-MET but affects targets downstream of c-MET.
In conclusion, Tivantinibis a highly selective c-Met tyrosine kinase inhibitor that has shown potential antitumor activity in HCC. Its effects on cell viability, apoptosis, and cell cycle arrest are independent of c-Met but involve downstream targets. Further research is needed to fully understand the mechanisms of action and potential therapeutic applications of tivantinib in HCC.
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