MET genetic lesions in non-small-cell lung cancer: pharmacological and clinical implications

Lung cancer is the leading cause of death for solid tumors worldwide with an annual mortality of over one million. Lung carcinoma includes a series of different diseases which are roughly divided into two groups based on clinical and histo-pathological features: non-small cell lung cancer (NSCLC), accounting for almost 80% of lung cancer diagnosis and small cell lung cancer (SCLC) responsible for the remaining 20%. The NSCLC molecular profile has been deeply investigated; alterations in several oncogenes, tumor suppressor genes and transcription factors have been detected, mainly in adenocarcinomas. Dissection of such a complex scenario represents a still open challenge for both researchers and clinicians. MET, the receptor for Hepatocyte Growth Factor (HGF), has been recently identified as a novel promising target in several human malignancies, including NSCLC. Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of EGFR with acquired resistance to EGFR tyrosine kinase inhibitors, MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET tyrosine kinases could be an effective strategy in this setting and led to the clinical investigation of multiple MET inhibitors in combination with anti-EGFR agents. Results from ongoing and future trials will clarify the role of anti-MET molecules for the treatment of NSCLC and will provide insights into the most appropriate timing for their use. The present review recapitulates the current knowledge on the role of MET signaling in NSCLC mainly focusing on its implications in molecular diagnostic approach and on the novel targeted inhibitors.