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

Nature Reviews Cancervolume 18pages341358 (2018) | Download Citation


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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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.

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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.

Author information


  1. Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Paolo M. Comoglio
  2. Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Livio Trusolino
  3. Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy

    • Carla Boccaccio
  4. Department of Oncology, University of Torino Medical School, Candiolo, Italy

    • Livio Trusolino
    •  & Carla Boccaccio


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

Competing interests

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.

Corresponding author

Correspondence to Paolo M. Comoglio.

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Lung sarcomatoid tumours

A poorly differentiated non-small-cell lung carcinoma that contains a component of sarcoma-like cells (that is, cells that display traits of mesenchymal differentiation).

Interstitial pressure

The pressure of fluid that flows out of capillaries and fills the space between the vascular system and cells.

Progression-free survival

(PFS). The time elapsed between the initiation of treatment and the onset of disease progression; measured both during and after therapy.

Overall survival

(OS). The time elapsed between the initiation of treatment and the death of the patient.

Matrix metalloproteinases

(MMPs). Zinc-dependent proteolytic enzymes secreted by cancer cells and stromal cells; these proteases degrade extracellular matrix (ECM) components, which facilitates cancer cell invasion, and cleave cell membrane-bound or ECM-associated precursor forms of many growth factors, thereby activating them and increasing their bioavailability in the tumour microenvironment.


Small extracellular vesicles secreted by multiple cell types that can be internalized by other cells. The transfer of the exosomal cargo (RNAs and proteins) may induce functional modifications in the recipient cells.


A type of cancer arising in the epithelial lining of biliary ducts.

Liquid biopsies

The sampling and analysis of nucleic acids or other circulating tumour-derived materials (including cancer cells and exosomes) present in biological fluids.

Array comparative genomic hybridization

A molecular cytogenetic technique that utilizes competitive hybridization of differently labelled probes to compare gene copy number differences between two genomes.

In situ hybridization

A cytogenetic method that uses DNA or RNA probes to visualize complementary DNA or RNA sequences in tissue sections.

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