Figure 1.

Targeted Inhibition of Hepatocyte Growth Factor (HGF)/c-Met Signaling in Head and Neck Squamous Cell Carcinoma (HNSCC). Secreted by local tumor associated fibroblasts (TAFs), pro-HGF is cleaved by membrane bound matriptase, enabling the heterodimer ligand to bind both the alpha and beta chain of the c-Met receptor. Upon binding, c-Met undergoes autophosphorylation and recruits adaptor molecules growth-factor-receptor-bound protein 2 (Grb2) and Grb2-associated binder 1 (Gab1) which further recruit oncogenic proteins SH2 containing protein tyrosine phosphatase (SHP2), signal transducers and activators of transcription-3 (STAT3), Ras/Raf, and phosphoinositide 3-kinase (PI3K), initiating signaling cascades promoting proliferation, migration, invasion, and metastasis. Inhibition of the pathway can be achieved through several strategies including anti-HGF monoclonal antibodies such as ficlatuzumab, the competitive HGF antagonist NK4, c-Met specific antibodies including onartuzumab, and c-Met tyrosine kinase inhibitors (TKIs) such as crizotinib. Italicized agents are in clinical development for HNSCC.