MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Abstract

Abstract:The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

KIF5B-MET Gene Rearrangement with Robust Antitumor Activity in Response to Crizotinib in Lung Adenocarcinoma

“…4 Oncogenic mutations in MET exon 14 splice sites can cause exon 14 skipping and lead to impaired Casitas B-cell lymphoma family E3 ubiquitin ligase binding and decreased MET degradation, which accounts for 3% to 4% of lung adenocarcinomas. 5 Clinical response to crizotinib or capmatinib has been reported previously in patients with MET exon 14 alterations. 6,7 Given the robust antitumor activity of crizotinib in a patient with KIF5B-MET gene rearrangement in our case, a subset of NSCLC could be generated by a fusion of KIF5B and MET, and this gene may thus be a promising molecular target for personalized diagnosis and treatment of LADC.…”

Forty‐nine gastric cancer cell lines with integrative genomic profiling for development of c‐MET inhibitor

“…Interestingly, Hs746T had higher expression of c‐Cbl than other MET ‐amplified cell lines. However, the expression of c‐Cbl did not affect the status of MET because Hs746T was found to have an exon 14 deletion, which is associated with a deletion of the juxtamembrane domain of MET with the Y1003 site, resulting in the loss of interaction with c‐Cbl …”

New Paradigms to Assess Consequences of Long-Term, Low-Dose Curcumin Exposure in Lung Cancer Cells

“…There is increasing emphasis on the importance of the c-Met/HGF pathway in lung cancer progression and promotion of resistance resulting from Met amplification, exon 14 mutation, or activation due to HGF expression [32][33][34], with small molecule Met inhibitors and anti-HGF antibodies now in clinical trials [35,36]. Exploring further mechanisms by which curcumin may inhibit HGF signalling in lung cancer should contribute to the mechanistic scrutiny applied when considering the utility of curcumin in therapeutic prevention regimens.…”