title: 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.
authors.affiliation: 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.
authors.forename: Conor A
authors.initials: CA
authors.lastname: Bradley
authors.affiliation: 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.
authors.forename: Manuel
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: University Paris Descartes, INSERM UMR-S1147, CNRS SNC 5014, Paris Sorbonne Cité Université, 45 rue des Saints-Pères 75006 Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.affiliation: Department of Oncology, University of Torino, SP 142 km 3.95, 10060 Candiolo (TO), Italy.|Candiolo Cancer Institute - Fondazione del Piemonte per l'fOncologia (FPO), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Strada Provinciale 142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: 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.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: 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.
authors.forename: Hajrah A
authors.initials: HA
authors.lastname: Khawaja
authors.affiliation: 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.
authors.forename: Mark
authors.initials: M
authors.lastname: Lawler
authors.affiliation: 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.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Van Schaeybroeck
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met