Targeting the HGF/c-MET pathway in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a significant cause of cancer-related morbidity and mortality worldwide. Despite improvements in local therapies, including surgical resection, liver transplantation, and transarterial embolization, the prognosis remains poor for the majority of patients who develop recurrence or present with advanced disease. Systemic therapy with the tyrosine kinase inhibitor sorafenib represents a milestone in advanced HCC but provides a limited survival benefit. Ongoing efforts to study hepatocarcinogenesis have identified an important role for c-MET signaling in the promotion of tumor growth, angiogenesis, and metastasis. In this review, we summarize the preclinical data from human tissue, cell lines, and animal models that implicate c-MET in the pathogenesis of HCC. We also evaluate potential biomarkers that may estimate prognosis or predict response to c-MET inhibitors for more rational clinical trial design. Finally, we discuss the latest clinical trials of c-MET inhibitors in advanced HCC.

Figure 1. Therapeutic Inhibitors of the c-MET Signaling Pathway

Binding of hepatocyte growth factor (HGF) to c-MET, homodimerization, and autophosphorylation (denoted by orange circles containing “P”) elicit downstream signaling mediated by adaptor proteins (Gab1 and Grb2) to induce activation of the phosphotidylinositol-3 kinase (PI3K), Ras/Raf/MEK/ERK, and the Cdc42/Rac1 pathways. HGF-independent signaling can be mediated by phosphorylated epidermal growth factor receptor (EGFR), which can be activated by its ligand transforming growth factor alpha (TGFα). Inhibitors of the HGF/c-MET signaling pathway are shown in yellow boxes with their corresponding targets denoted. Inhibitors in bold have completed phase II trials in advanced HCC.