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  • Review Article
  • Published:

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

Nature Reviews Clinical Oncology volume 14, pages 562–576 (2017)Cite this article

Subjects

A Corrigendum to this article was published on 23 January 2018

Key Points

  • Aberrant c-MET pathway activation occurs frequently in gastrointestinal tumours and can result from multiple mechanisms, including c-MET protein overexpression, MET amplification or enhanced transcription and/or aberrant autocrine or paracrine secretion of HGF

  • Activated c-MET signalling results in enhanced cancer cell proliferation, survival and invasion; furthermore, a complex network of signalling involving other receptors enhances the potency and endurance of c-MET downstream signalling

  • Elevated c-MET expression/amplification has been associated with a poor clinical outcome in patients with gastro-oesophageal tumours, although conflicting reports exist with respect to a prognostic role of c-MET in colorectal cancer

  • Structural studies of HGF and c-MET have yielded important results that paved the way for the development of anti-HGF and anti-c-MET monoclonal antibodies and specific or nonspecific c-MET tyrosine kinase inhibitors

  • In contrast to the initial phase II studies, the phase III trials failed to show any clinical benefit from anti-HGF or anti-c-MET therapies in gastrointestinal tumours, even in patients with c-MET-positive disease

  • Additional biomarkers should be sought, using techniques such as MET RNA in situ hybridization (ISH) and MET single/double silver ISH and 'omics'-based approaches to identify patients that are likely to derive maximal benefits from anti-HGF/c-MET therapies

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.

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Figure 1: The multidomain structure of c-MET and its ligand, HGF.
Figure 2: HGF/c-MET signalling pathway components, interaction network, and mechanisms of negative regulation.
Figure 3: Deregulation of the HGF/c-MET pathway in colorectal cancer and gastric cancer.
Figure 4: Stratification biomarkers to identify MET-dependent colorectal cancers (CRCs).
Figure 5: HGF/c-MET inhibitors in clinical trials.

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Acknowledgements

This work was supported by MErCuRIC, funded by the European Commission's Framework Programme 7, under contract #602901.

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Authors and Affiliations

  1. Drug Resistance Group, Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, 97 Lisburn Road, BT9 7AE, Belfast, UK

    Conor A. Bradley, Manuel Salto-Tellez, Hajrah A. Khawaja, Mark Lawler, Patrick G. Johnston & Sandra Van Schaeybroeck

  2. Northern Ireland Molecular Pathology Lab, Belfast Health and Social Care Trust, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK

    Manuel Salto-Tellez

  3. University Paris Descartes, INSERM UMR-S1147, CNRS SNC 5014, Paris Sorbonne Cite Universite, 45 rue des Saints-Peres, Paris, 75006, France

    Pierre Laurent-Puig

  4. Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Torino, Italy

    Alberto Bardelli

  5. 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, Torino, 10060, Candiolo, Italy

    Alberto Bardelli

  6. Phase I - Early Clinical Trials Unit, Antwerp University Hospital,

    Christian Rolfo

  7. Wilrijkstraat 10, 2650, Edegem (Antwerp), Belgium

    Christian Rolfo

  8. Center for Oncological Research, University of Antwerp,

    Christian Rolfo

  9. Universiteitsplein 1, Wilrijk (Antwerp), 2610, Belgium

    Christian Rolfo

  10. Medical Oncology Department, Vall d'fHebron University Hospital, Vall d'fHebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, P. Vall d'fHebron 119–129, Barcelona, 08035, Spain

    Josep Tabernero

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Correspondence to Sandra Van Schaeybroeck.

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Competing interests

P.L.P. has received honoraria from Amgen, Astrazeneca Boerhinger–Ingelheim, Integragen, Merck–Serono, Roche and Sanofi. J.T. has served on the advisory boards of Amgen, Bayer, Boehringer–Ingelheim, Celgene, Chugai, Lilly, MSD, Merck–Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. P.G.J. is the founder and holds shares in Almac diagnostics, Fusion and CV6 Therapeutics, and has served as an expert adviser/consultant of Pfizer and Chugai Pharmaceuticals. The other authors declare no competing interests.

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Bradley, C., Salto-Tellez, M., Laurent-Puig, P. et al. Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol 14, 562–576 (2017). https://doi.org/10.1038/nrclinonc.2017.40

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