<p><em>MET</em> Inhibitors for the Treatment of Gastric Cancer: What’s Their Potential?</p>

Abstract

Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.

The Role of HGF/MET Signaling in Metastatic Uveal Melanoma

“…In this regard, cancer cells which have exon 14 skipping are sensitive to a MET inhibitor [39]. In addition to alterations, overexpression and gene amplification of MET is present in a variety of tumors and have been shown to correlate with poor prognosis [40,41]. HGF/MET signaling mediates the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), PI3K/protein kinase B (AKT), focal adhesion kinase (FAK), and STAT3/5 signaling pathway (Figure 2).…”

Novel Biomarkers of Gastric Adenocarcinoma: Current Research and Future Perspectives

“…An aberrant, overactivated MET pathway promotes disease progression, and serves as a common mechanism of resistance to HER -targeted therapy. Beyond anti-HER2 therapy, the MET pathway seems to be a culprit of cancer invasiveness, with MET-overexpressing tumors having poorer prognosis [ 97 ].…”

Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View

“…The MET gene encodes Hepatocyte Growth Factor (HGF) receptor, which is a member of the receptor tyrosine kinase family involved in the regulation of cell growth and differentiation in health and disease. In gastric cancer, MET represents a major oncogenic driver (i.e., proto-oncogene), and activation of the pathway promotes disease progression [83] as well as resistance to HER2-targeted treatment strategies [84] and represents an adverse prognostic factor [85]. Important growth-promoting downstream pathways are activated by MET, such as the PI3K/AKT/mTOR pathway the RAS/RAF/ERK/MAPK pathway, the STAT-3 pathway and NFkB.…”

“…In the VIKTORY umbrella trial, there was a promising signal (i.e., ORR 50%) for the activity of the MET inhibitor Savolitinib in gastric cancer patients, and this compound is currently under further clinical development [91]. Mostly, however, efficacy of MET targeting TKI was marginal [83].…”

“…Key factors contributing to the disappointing results thus far are related to the heterogeneity of target expression found in gastric cancer, difficulties in reliably measuring MET overexpression/activation, and the activation of alternative signaling pathways specifically in the TCGA CIN subgroup, characterized by multiple concurrent amplifications in related pathways [83]. Moreover, translational research data from studies related to the VIKTORY trial indicated that novel occurring mutations in MET (i.e., MET D1228V/N/H and Y1230C) or high copy number MET gene amplifications contribute to the development of resistance against Savolitinib, which can be identified in the circulating tumor DNA (ctDNA) from blood samples [92].…”