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. Access

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MET-DEPENDENT SOLID TUMOURS — MOLECULAR DIAGNOSIS AND TARGETED THERAPY Article 08 June 2020 KRAS MUTATION: FROM UNDRUGGABLE TO DRUGGABLE IN CANCER Article Open access 15 November 2021

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lung cancer (NSCLC). _J. Clin. Oncol._ 34, 9020–9020 (2016). Article  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS,

Candiolo, Italy Paolo M. Comoglio * Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy Livio Trusolino * Cancer Stem Cell Research, Candiolo Cancer

Institute, FPO-IRCCS, Candiolo, Italy Carla Boccaccio * Department of Oncology, University of Torino Medical School, Candiolo, Italy Livio Trusolino & Carla Boccaccio Authors * Paolo M.

Comoglio View author publications You can also search for this author inPubMed Google Scholar * Livio Trusolino View author publications You can also search for this author inPubMed Google

Scholar * Carla Boccaccio View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS P.M.C., L.T. and C.B. contributed equally to writing and

reviewing the manuscript. CORRESPONDING AUTHOR Correspondence to Paolo M. Comoglio. ETHICS DECLARATIONS 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. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

claims in published maps and institutional affiliations. REVIEWER INFORMATION _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/ ELECTRONIC SUPPLEMENTARY MATERIAL SUPPLEMENTARY TABLE 1 SUPPLEMENTARY TABLE 2 GLOSSARY * 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. *

Exosomes 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. * Cholangiocarcinomas 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. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Published: 19 April 2018 * Issue Date: June 2018 * DOI: https://doi.org/10.1038/s41568-018-0002-y SHARE THIS ARTICLE Anyone you

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