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Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy

Abstract

The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered (‘oncogene addiction’) and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions (‘oncogene expedience’). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells (‘oncogene inherence’). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.

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Fig. 1: MET structural alterations and oncogene addiction.
Fig. 2: MET oncogene expedience.
Fig. 3: Stromal HGF protects cancer cells from targeted therapy.
Fig. 4: The MET oncogene in cancer stem cells: a paradigm of inherence.

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Acknowledgements

The authors thank J. M. Hughes for clinical trial database mining, L. Lanzetti for micrographs and M. Milan for scrutiny of MET mutations. The authors also thank A. Cignetto, D. Gramaglia and F. Natale for excellent assistance. Work in the authors’ laboratories is supported by the Italian Association for Cancer Research (‘Special Program Molecular Clinical Oncology 5 × 1000, N. 9970’ and investigator grants N. 15572 to P.M.C., N. 18532 to L.T. and N. 15709 and N. 19933 to C.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS (5 × 1000 Italian Ministry of Health 2011 and 2014); Italian Ministry of Health (Ricerca Corrente); Transcan, TACTIC; and Comitato per Albi98.

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P.M.C., L.T. and C.B. contributed equally to writing and reviewing the manuscript.

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Correspondence to Paolo M. Comoglio.

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P.M.C. is co-founder and scientific adviser of Octimet Oncology NV and Metis Precision Medicine B-Corp. C.B. and L.T. declare no competing interests.

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Nature Reviews Cancer thanks G. Vande Woude, K. Matsumoto and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Related links

Candiolo Cancer Institute: http://www.ircc.it/

COSMIC catalogue of human mutations in cancer: http://cancer.sanger.ac.uk/cosmic

Report from Aveo Pharmaceuticals Inc.: https://www.sec.gov/Archives/edgar/data/1325879/000119312516706645/d249918d8k.htm

US National Institutes of Health — ClinicalTrials.gov: https://clinicaltrials.gov/

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Comoglio, P.M., Trusolino, L. & Boccaccio, C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer 18, 341–358 (2018). https://doi.org/10.1038/s41568-018-0002-y

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