CMET Exon 14 Skipping: From the Structure to the Clinic

Abstract

The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility, and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non–small cell lung cancer. In particular, several cMET inhibitors have been developed as innovative therapeutic candidates and are currently under investigation in clinical trials. However, one of the challenges in establishing effective targeted treatments against cMET remains the accurate identification of biomarkers for the selection of responsive subsets of patients. Recently, splice site mutations have been discovered in cMET that lead to the skipping of exon 14, impairing the breakdown of the receptor. Patients with NSCLC who are carrying this splice variant typically overexpress the cMET receptor and show a response to small molecule inhibitors of cMET. Here, we review the main differences at the structural level between the wild-type and the splice variants of cMET and their influence on cMET signaling. We clarify the reason why this variant responds to small molecule inhibitors and their prognostic/predictive role.