The role of the c-Met pathway in lung cancer and the potential for targeted therapy

Abstract

Hepatocyte growth factor receptor (HGFR), the product of the MET gene, plays an important role in normal cellular function and oncogenesis. In cancer, HGFR has been implicated in cellular proliferation, cell survival, invasion, cell motility, metastasis and angiogenesis. Activation of HGFR can occur through binding to its ligand, hepatocyte growth factor (HGF), overexpression/amplification, mutation, and/or decreased degradation. Amplification of HGFR can occur de novo or in resistance to therapy. Mutations of HGFR have been described in the tyrosine kinase domain, juxtamembrane domain, or semaphorin domain in a number of tumors. These mutations appear to have gain of function, and also reflect differential sensitivity to therapeutic inhibition. There have been various drugs developed to target HGFR, including antibodies to HGFR/HGF, small-molecule inhibitors against the tyrosine kinase domain of HGFR and downstream targets. Different HGFR inhibitors are currently in clinical trials in lung cancer and a number of solid tumors. Several phase I trials have already been completed, and two specific trials have been reported combining HGFR with epidermal growth factor receptor (EGFR) inhibition in non-small cell lung cancer. In particular, trials involving MetMAb and ARQ197 (tivantinib) have gained interest. Ultimately, as individualized therapies become a reality for cancers, HGFR will be an important molecular target.

Inhibition of Tumor Growth and Metastasis in Non–Small Cell Lung Cancer by LY2801653, an Inhibitor of Several Oncokinases, Including MET

“…The dysregulation of MET signaling has been extensively described in many types of human cancers including NSCLCs (8)(9)(10)(11)(12). The sustained activation, overexpression, mutation, or gene amplification of MET is generally associated with a worse prognosis and contributes to tumor growth, angiogenesis, and metastasis.…”

“…Aberrant MET activation can occur through HGF-dependent or -independent mechanisms. Because of the contribution of this pathway to the regulation of a large network of signaling cascades, it has been implicated to play important roles in tumor cell proliferation, survival, motility, invasion, angiogenesis, and metastasis (9). The constitutive activation of MET may occur in cancer cells via a number of mechanisms including overexpression (with or without gene amplification), activating mutation, HGF autocrine/paracrine stimulation, or through crosstalk with other RTKs (10,11).…”

“…The constitutive activation of MET may occur in cancer cells via a number of mechanisms including overexpression (with or without gene amplification), activating mutation, HGF autocrine/paracrine stimulation, or through crosstalk with other RTKs (10,11). Sustained MET activation is associated with poor outcomes for several cancer types including NSCLCs (9,12).…”

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

“…The sema domains are necessary for the dimerization, activation, and regulation of c-Met, and may be targeted for therapeutic treatment in c-Met dependent cancers that are regulated by activating mutations of MET. Mutations in the sema domain are often seen in lung cancers and nearly 7% of mesothelioma patients (N375S, M431V, and N454I) [38]. However, additional research is needed to unveil the exact functional role of the various MET mutations mentioned above.…”

“…This c-CBL binding leads to the internalization of the c-Met receptor via clathrin-coated vesicles [14]. However, when the Y1003 position is mutated, the HGF receptor is not ubiquitinated, resulting in decreased lysosomal degradation, increased stability and additional oncogenic activation [38]. Mutations of the JM domain are associated with SCLC (S1040P, T992I, and R970C) as well as other cancers including melanoma (N930S) and gastric carcinoma (P991S) [14].…”