c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma

Abstract

c-MET is the membrane receptor for hepatocyte growth factor (HGF), also known as scatter factor or tumor cytotoxic factor, a mitogenic growth factor for hepatocytes. HGF is mainly produced by cells of mesenchymal origin and it mainly acts on neighboring epidermal and endothelial cells, regulating epithelial growth and morphogenesis. HGF/MET signaling has been identified among the drivers of tumorigenesis in human cancers. As such, c-MET is a recognized druggable target, and against it, targeted agents are currently under clinical investigation. c-MET overexpression is a common event in a wide range of human malignancies, including gastric, lung, breast, ovary, colon, kidney, thyroid, and liver carcinomas. Despite c-MET overexpression being reported by a large majority of studies, no evidence for a c-MET oncogenic addiction exists in hepatocellular carcinoma (HCC). In particular, c-MET amplification is a rare event, accounting for 4%-5% of cases while no mutation has been identified in c-MET oncogene in HCC. Thus, the selection of patient subgroups more likely to benefit from c-MET inhibition is challenging. Notwithstanding, c-MET overexpression was reported to be associated with increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition. Here we summarize the role of activated HGF/MET signaling in HCC, its prognostic relevance, and the implications for therapeutic approaches in HCC.

Keywords: c-MET; clinical trials; hepatocellular carcinoma.

Figure 1

c-MET activation signaling pathways. Abbreviations: AKT, protein kinase B; CD44, cell differentiation molecule 44; CDC42, cell division control protein 42 homolog; EGFR, epidermal growth factor receptor; ERK, extracellular-signal-regulated kinase; FAS-L, FAS ligand; HER2, human epidermal growth factor receptor 2; HGF, hepatocyte growth factor; IL, interleukin; mTOR, mammalian target of rapamycin; p53, tumor protein p53; PI3K, phosphoinositide 3-kinase; TGF-β, transforming growth factor beta; TNF-α, tumor necrosis factor alpha; VEGFR, vascular endothelial growth factor receptor.