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J Natl Cancer Inst. 2017 May 1;109(5). doi: 10.1093/jnci/djw262.

Exon 14 Deleted MET Receptor as a New Biomarker and Target in Cancers.

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UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, CNRS, Institut Pasteur de Lille, Univ. Lille, Lille, France.
Thoracic Oncology Department, CHU Lille, Univ. Lille, Lille, France.
Division of Biochemistry and Molecular Biology, Oncology and Molecular Genetics Laboratory, CHU Lille, Lille, France.
Service de Pneumologie, Hôpital Tenon, AP-HP, Paris, France.


Inhibitors of the receptor tyrosine kinase (RTK) MET have been ineffective at treating cancer, possibly because of lack of knowledge that would allow selection of tumors likely to respond to this treatment. In contrast, specific epidermal growth factor receptor (EGFR) inhibitors have been used successfully against lung tumors displaying activating mutations in the kinase domain of EGFR. Recent publications describe a set of mutations causing MET exon 14 skipping, and importantly, several case reports describe objective responses to MET-targeting tyrosine kinase inhibitors in patients with such mutations. These observations suggest a novel therapeutic strategy for fighting cancer, especially in the lung. Exon 14 encodes the MET juxtamembrane domain targeted by mechanisms that negatively regulate receptor stability and activity. In this review, we describe the molecular mechanisms leading first to exon 14 skipping and then to activation of the MET receptor and how this process differs from that triggered by classical RTK-activating mutations in the kinase domain. We detail the clinical characteristics of patients carrying these mutations and the sensitivity of their tumors to MET inhibitors. Lastly, we discuss future challenges related to MET mutations in cancers, including patient screening and anticipating resistance to MET inhibitors.

[Indexed for MEDLINE]

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