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Nat Rev Clin Oncol. 2017 Sep;14(9):562-576. doi: 10.1038/nrclinonc.2017.40. Epub 2017 Apr 4.

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

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Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
Northern Ireland Molecular Pathology Lab, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, UK.
University Paris Descartes, INSERM UMR-S1147, CNRS SNC 5014, Paris Sorbonne Cité Université, 45 rue des Saints-Pères 75006 Paris, France.
Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy.
Phase I - Early Clinical Trials Unit, Antwerp University Hospital; Wilrijkstraat 10, 2650 Edegem (Antwerp), Belgium.
Center for Oncological Research, University of Antwerp; Universiteitsplein 1, 2610 Wilrijk (Antwerp) Belgium.
Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, P. Vall d'Hebron 119-129, 08035 Barcelona, Spain.


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.

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