Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges

Abstract

Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)-hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

“…Accumulation of c-MET responds to HGF treatment as a result of stimulus-dependent endocytosis, intracellular trafficking and degradation 29. Addition of HGF resulted in a time-dependent regulation of c-MET protein levels, which was sensitive to the proteasome inhibitor MG132, indicating that HGF-dependent degradation was active in PANC-1 (figure 7F).…”

“…Various signalling pathways are activated on HGF binding to c-MET receptor, which trigger different cellular responses 29. Among them, activation of the mitogen-activated protein kinase signalling cascade, as well as its downstream target extracellular signal-regulated kinase (ERK), is involved in cell proliferation.…”

“…The regulation of c-MET stability is a complex process in which different effectors might play a role depending on the cellular context 29. In the case of pancreatic tumour cells, the mechanisms regulating c-MET stability are poorly understood; therefore, the DYRK1A (or DYRK1B) roles in this process will need further investigation.…”

Metabolomics reveals tepotinib‐related mitochondrial dysfunction in MET‐activating mutations‐driven models

“…Distinct MET-activating mutations are characterized by different metabolic profiles Numerous preclinical studies and clinical trials are evaluating MET as a potential therapeutic target [16,17]. Detailed understanding of less documented aspects of MET targeting, such as impact on cellular metabolism or immune response, will become particularly important for their successful clinical use.…”

Cell-Free DNA Profiling to Discover Mechanisms of Exceptional Response to Cabozantinib Plus Panitumumab in a Patient With Treatment Refractory Metastatic Colorectal Cancer

“…Many of these are under different stages of clinical evaluation, either alone or in combination with other targeted therapy in patients with advanced solid tumors (40, 41). The MErCuRIC phase I/II clinical trial aims to assess the safety and efficacy of the combination of crizotinib and a MEK1/2 inhibitor, binemetinib, in patients with MET over-expressing, RAS-mutant or RAS wild-type metastatic CRC (42).…”