Recent developments of c‐Met as a therapeutic target in hepatocellular carcinoma

Abstract

Aberrant c‐Met activity has been implicated in the development of hepatocellular carcinoma (HCC), suggesting that c‐Met inhibition may have therapeutic potential. However, clinical trials of nonselective kinase inhibitors with c‐Met activity (tivantinib, cabozantinib, foretinib, and golvatinib) in patients with HCC have failed so far to demonstrate significant efficacy. This lack of observed efficacy is likely due to several factors, including trial design, lack of patient selection according to tumor c‐Met status, and the prevalent off‐target activity of these agents, which may indicate that c‐Met inhibition is incomplete. In contrast, selective c‐Met inhibitors (tepotinib, capmatinib) can be dosed at a level predicted to achieve complete inhibition of tumor c‐Met activity. Moreover, results from early trials can be used to optimize the design of clinical trials of these agents. Preliminary results suggest that selective c‐Met inhibitors have antitumor activity in HCC, with acceptable safety and tolerability in patients with Child‐Pugh A liver function. Ongoing trials have been designed to assess the efficacy and safety of selective c‐Met inhibition compared with standard therapy in patients with HCC that were selected based on tumor c‐Met status. Thus, c‐Met inhibition continues to be an active area of research in HCC, with well‐designed trials in progress to investigate the benefit of selective c‐Met inhibitors. (Hepatology 2018;67:1132–1149)

Increased expression of hematological and neurological expressed 1 (HN1) is associated with a poor prognosis of hepatocellular carcinoma and its knockdown inhibits cell growth and migration partly by down‐regulation of c‐Met

“…c‐Met, a famous oncogene, has been demonstrated to promote the HCC progression, and been developed as a therapeutic target in HCC . We found that HN1 expression was positively correlated with c‐Met expression in these four HCC cell line.…”

“…Previously, decreased expression of c‐Met was also detected in the HN1‐depleted melanoma cells . c‐Met, the receptor tyrosine kinase (RTK) of HGF, has been demonstrated to promote the HCC progression . The expression of c‐Met was closely associated with early recurrence .…”

Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma

“…We identified around 22% of potentially targetable genetic alterations in advanced HCC, mainly including alterations of AKT/mTOR and the MET pathway or ligand amplification, such as VEGFA and FGF19 . The MET pathway has been considered an appealing target in patients with advanced HCC . 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 .…”

“…The MET pathway has been considered an appealing target in patients with advanced HCC. (22) 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. (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.…”

Searching for the link; mechanisms underlying liver regeneration and recurrence of colorectal liver metastasis post partial hepatectomy

“…Furthermore, overexpression of c‐Met is associated with vascular invasion, tumor growth, and poor prognosis in cancer patients . Subsequently, targeting c‐Met has become a major strategy for novel cancer treatment, and numerous clinical trials are currently underway trialing the effect of monoclonal antibodies and small molecule inhibitors of c‐Met (reviewed by Bouattour et al …”