Response to Crizotinib in a Patient With Lung Adenocarcinoma Harboring a MET Splice Site Mutation

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MET (c-MET; mesenchymal-epithelial transition factor) is a receptor tyrosine kinase that was first characterized as a proto-oncogene in 1984, in a chemically transformed osteosarcoma cell line [1]. Located on chromosome 7q21-31, the MET gene encodes a cell surface receptor tyrosine kinase comprised of a 50-kDa α-chain and a 140-kDa transmembrane β-chain linked by a disulfide bond. The natural ligand for cMet is hepatocyte growth factor (HGF), also known as scatter factor [2]. Following binding of HGF the c-MET receptor undergoes dimerization and phosphorylation, which in turn promotes recruitment of downstream effector proteins, leading to activation of multiple signaling cascades, including the MAPK, PI3K/Akt, STAT and NF-κB pathways [3]. Physiologic roles for HGF/MET signaling include embryogenesis, development, and wound healing [3–5]. Aberrant activation of the c-Met receptor tyrosine kinase promotes oncogenicity in a subset of lung adenocarcinomas. A variety of mechanisms can result in constitutive c-Met signaling, including MET gene amplification, protein overexpression, activating point mutations, and induction of its ligand HGF [3, 6, 7]. Crizotinib, a multitargeted tyrosine kinase inhibitor (TKI) that is FDA approved for the therapy of lung adenocarcinomas harboring ALK or ROS1 fusions [8–10], was also recently found to be clinically active in tumors with high level MET amplification [11]. These findings have prompted the clinical development of more selective c-MET inhibitors for evaluation in this particular patient population. MET splice site mutation has also been demonstrated to induce constitutive activity and confer sensitivity to c-Met inhibition in vitro [12, 13]. Indeed, frequent activating MET splice site mutations were recently described in whole exome sequencing (WES) discovery efforts in lung adenocarcinoma [14]. However, the clinical activity of c-Met inhibition in this context remains unknown. We identified one such mutation using targeted next generation sequencing (NGS) in a patient with lung adenocarcinoma and treated him with crizotinib.