Targeting the hepatocyte growth factor-cMET axis in cancer therapy

Abstract

The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non-small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.

Fig 1.

The hepatocyte growth factor (HGF)–cMET axis signaling network and ongoing targeted therapy strategies. The pathway, which transduces invasive growth signals from mesenchymal to epithelial cells (secreted by mesenchymal cells), is activated by HGFA and binds to the cMET receptor on epithelial cells. cMET kinase activation results in trans-autophosphorylation and binding of adaptor proteins, forming scaffolds for recruitment and activation of signaling proteins. Signals generated from these structures lead to activation of signaling pathways related to increased proliferation, survival, motility, invasiveness, and stimulation of angiogenesis. EGFR, epidermal growth factor receptor; FAK, focal adhesion kinase; GRB2, growth factor receptor–bound protein 2; HER, human epidermal growth factor receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; RAS, renin–angiotensin system; STAT, signal transducer and activator of transcription.

Fig 2.

Protein overexpression by immunohistochemistry, a molecular aberration in the cMET receptor evaluated to select patients for anti–hepatocyte growth factor–cMET axis–targeted therapies.

Fig 3.

Gene amplification by fluorescent in situ hybridization, a molecular aberration in the cMET receptor evaluated to select patients for anti–hepatocyte growth factor–cMET axis–targeted therapies. (A) Nonamplified; (B) amplified.

Fig A1.

Activating mutations by Sequenom (San Diego, CA), molecular aberrations in the cMET receptor evaluated to select patients for anti–hepatocyte growth factor–cMET axis–targeted therapies.