title: 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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Department of Pathology, Antwerp University Hospital, Edegem, Antwerp, Belgium; Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Van Der Steen
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands; Cancer Pharmacology Lab, Italian Association for Cancer Research Start-Up Unit, University of Pisa, Hospital of Cisanello, Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: Department of Pathology, Antwerp University Hospital, Edegem, Antwerp, Belgium; Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
authors.affiliation: Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Oncology, Tuscan Tumor Institute, Florence, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
authors.affiliation: Division of Medical Oncology, University of Colorado, Aurora, Colorado.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium; Phase I Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital, Antwerp, Belgium. Electronic address: christian.rolfo@uza.be.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
mesh_terms: D005091:Exons; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D012326:RNA Splicing; D015398:Signal Transduction
chemical_list: D019859:Proto-Oncogene Proteins c-met
keywords: Exon 14 skipping; NSCLC; Targeted therapies; cMET