The potential roles of hepatocyte growth factor (HGF)-MET pathway inhibitors in cancer treatment

Abstract

MET is located on chromosome 7q31 and is a proto-oncogene that encodes for hepatocyte growth factor (HGF) receptor, a member of the receptor tyrosine kinase (RTK) family. HGF, also known as scatter factor (SF), is the only known ligand for MET. MET is a master regulator of cell growth and division (mitogenesis), mobility (motogenesis), and differentiation (morphogenesis); it plays an important role in normal development and tissue regeneration. The HGF-MET axis is frequently dysregulated in cancer by MET gene amplification, translocation, and mutation, or by MET or HGF protein overexpression. MET dysregulation is associated with an increased propensity for metastatic disease and poor overall prognosis across multiple tumor types. Targeting the dysregulated HGF-MET pathway is an area of active research; a number of monoclonal antibodies to HGF and MET, as well as small molecule inhibitors of MET, are under development. This review summarizes the key biological features of the HGF-MET axis, its dysregulation in cancer, and the therapeutic agents targeting the HGF-MET axis, which are in development.

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

“…The HGF/HGF receptor c-Met axis has been defined as a potential target in cancer therapy of various tumor entities [7,8,9,10]. In this study, we aimed to investigate whether single c-Met inhibition is sufficient to inhibit neuroendocrine tumor cell growth and migration in vitro, and to further characterize the role of the HGF/c-Met axis in neuroendocrine tumors.…”

“…6). Accordingly, c-Met inhibitors have been reported to inhibit downstream Akt and MAPK signaling cascades in various tumors [7,9,46]. Inhibition of Akt/mTOR signaling is a proven, important target in neuroendocrine tumor cells [28,30].…”

“…The endogenous ligand of c-Met is HGF. The HGF/c-Met axis has been characterized as an important target in cancer therapy [7,8,9,10] as it mediates tumor cell growth, migration and metastasis. Extracellular anti-HGF antibodies, anti-Met antibodies, as well as ATP-competitive and non-ATP competitive MET inhibitors have been developed and are in clinical trial programs [7,9].…”

“…The HGF/c-Met axis has been characterized as an important target in cancer therapy [7,8,9,10] as it mediates tumor cell growth, migration and metastasis. Extracellular anti-HGF antibodies, anti-Met antibodies, as well as ATP-competitive and non-ATP competitive MET inhibitors have been developed and are in clinical trial programs [7,9]. Cabozantinib (XL-184) is an ATP-competitive multi-TKI (with activity against c-Met, VEGFR2, c-KIT, FLT3, RET and TIE2) that has recently been approved by the FDA and EMEA for the treatment of medullary thyroid carcinoma [11,12].…”

MicroRNAs and Long Non-coding RNAs in c-Met-Regulated Cancers

“…Binding of HGF can initiate stable c-Met homodimerization, which is mediated by adaptor proteins (GAB1 and GRB2), and then activates a number of key signaling pathways, including PI3K/Akt, Erk1/2, JAK/STAT, Src, Ras/MAPK, and Wnt/β-catenin (Imura et al, 2016;Pilotto et al, 2017), to induce cell proliferation, migration, invasion, and other biological effects (Ponzetto et al, 1994;Johnson and Lapadat, 2002) (Figure 1A). The HGF/c-Met axis is involved in biological and pathological processes such as embryogenesis, wound healing, and hepatic renal and epidermis regeneration (Parikh et al, 2014). The oncogenicity of c-Met is rarely caused by genetic alteration, and is more often due to upregulation of the wild-type gene (Trusolino et al, 2010;Gherardi et al, 2012).…”