MET Oncogene in Non-Small Cell Lung Cancer: Mechanism of MET Dysregulation and Agents Targeting the HGF/c-Met Axis

Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and has a poor prognosis. Current treatments for advanced NSCLC included traditional chemotherapy, radiotherapy, targeted therapy, and immunotherapy. The efficacy of targeted therapy relies on oncogene addiction. Mesenchymal-epithelial transition factor (MET) gene can encode unconventional receptor tyrosine kinases with pleiotropic functions, when signals are abnormally activated, it can initiate and maintain tumor transformation, promote cell proliferation, survival, tumor invasion and angiogenesis. Thus, it is a promising therapeutic target. Previous studies have shown that elevated levels of HGF and/or overexpression of c-Met are associated with poor prognosis in lung cancer. In preclinical and clinical trials, c-MET inhibitors have shown some antitumor activity in NSCLC. Although the efficacy results of MET inhibitors in Phase III clinical trials are disappointing, given the molecular heterogeneity of NSCLC, only subgroups of patients with MET gene alterations may benefit from c-MET inhibitors. The challenge for the future is to screen out the potential beneficiaries. To solve this problem, there is need for large data analysis for the detection methods and treatment effects, to establish standards that meet the MET activation status, and determine reliable thresholds to achieve effective patient stratification and clinical decision making. This article summarized the structure of the hepatocyte growth factor (HGF)/c-Met axis, the different mechanisms of MET addiction, as well as MET amplification as acquired resistance mechanism to epidermal growth factor receptor-tyrosine kinase inhibitors, the latest advances of MET inhibitors, and immuotherapy in the treatment of NSCLC with MET alterations.

Keywords: c-mesenchymal-epithelial transition; non-small cell lung cancer; oncogene addiction; receptor tyrosine kinases; treatment.

Figure 1

Major Mechanism of MET/HGF axis dysregulation. The extracellular portion of c-MET consists of a four immunoglobulin (Ig)-like modules, a cysteine-rich, MET-related sequence domain, and a Sema domain (homologous to semaphorin) responsible for binding to HGF. The intracellular portion of c-MET consists of the paramembrane domain, the Catalytic domain, and the Docking site responsible for signal transduction. Various mechanisms of MET/HGF axis addiction in NSCLC, including MET/HGF overexpression, and MET gene alterations (including point mutations, amplification, and fusion). A number of drugs targeting MET (small molecule TKIs, MET antibody, and HGF antibody) have been studied. MET, c-mesenchymal-epithelial transition factor; HGF, hepatocyte growth factor; NSCLC, non-small cell lung cancer.