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

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.

Novel Emerging Molecular Targets in Non-Small Cell Lung Cancer

“…The METex1 4 skipping mutations alter the splicing process, producing a MET variant that lacks Y1003, which consequently cannot bind Cbl. This alteration results in decreased degradation and subsequent ligand-independent MET activation [ 17 ].…”

“…Amplification of MET is the main resistance mechanism to EGFR-TKIs in NSCLC patients, both for the first- and second-generations (50–60%) and for the third-generation (15–20%) [ 17 ]. Several ongoing trials are investigating the role of MET-TKIs as a single agent or in combination with EGFR-TKIs, to overcome the acquired resistance to anti-EGFR therapies ( Table 2 ).…”

“…The MET activation has shown to induce programmed cell-death protein-1–ligand-1 (PD-L1) expression, contributing to immune suppression and evasion [ 33 ]. Several retrospective analyses have reported controversial results on the predictive value of MET alterations to immunotherapy [ 10 , 17 ]. In the IMMUNOTARGET study, 36 MET -positive NSCLC patients receiving immunotherapy experienced limited activity (ORR 16%) and survival outcomes (mPFS and mOS of 3.4 and 18.4 months, respectively), similar to other analyses [ 34 , 35 ].…”

“…Moreover, PD-L1 and tumor mutational burden (TMB) seemed not to predict response to immunotherapy in these patients [ 9 ]. Therefore, immunotherapy should be considered only after failure of other effective treatments, although the role of immune-based combinations in this setting needs further investigation [ 17 ]. In this context, several Phase I–II trials on the combination of MET-TKIs and immunotherapy are ongoing (e.g., NCT02323126, NCT03468985).…”

Overview of current targeted therapy in gallbladder cancer

“…Elevated MET was associated with poor prognosis in liver cancer, breast cancer, pancreatic cancer, gastric cancer, NSCLC, cervical cancer, and colorectal cancer. 79,[276][277][278][279][280][281][282][283][284][285] In GBC, MET overexpression ranged from 5 to 74% of patients, and was also associated with clinical poor outcome. [286][287][288][289][290] The conclusion was further supported by different groups that found a similar correlation.…”