Targeting the MET-Signaling Pathway in Non-Small–Cell Lung Cancer: Evidence to Date

Olivier Bylicki,1,2 Nicolas Paleiron,1 Jean-Baptiste Assié,2– 4 Christos Chouaïd2,3 1Respiratory Disease Unit, HIA Sainte Anne, Toulon, France; 2University Paris–Est Créteil (UPEC), CEpiA (Clinical Epidemiology and Ageing), EA 7376- IMRB, UPEC, Créteil, France; 3Pneumology Department, Centre Hospitalier Intercommunal De Créteil, Créteil, France; 4Cordeliers Research Center, Inserm, Functional Genomics of Solid Tumors Laboratory, Sorbonne University, University of Paris, Paris, FranceCorrespondence: Olivier BylickiRespiratory Disease Unit, HIA Sainte Anne, BRCM Toulon, 2, Boulevard Saint-Anne, Toulon 83000, FranceTel +33(0)483162937Fax +33(0)483162461Email olivier.bylicki@intradef.gouv.frAbstract: The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small–cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next-generation sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation.Keywords: non-small–cell lung cancer, MET exon 14, MET amplification, MET pathway