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Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14
Paul K Paik1, Alexander Drilon2, Pang-Dian Fan3
1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. paikp@mskcc.org.
Unlabelled:
Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the CBL E3-ubiquitin ligase-binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.
Significance:
Oncogenic mutations in the MET exon 14 splice sites that cause exon 14 skipping occur in 4% of lung adenocarcinomas. We report responses to the MET inhibitors crizotinib and cabozantinib in patients with lung adenocarcinomas harboring MET exon 14 splice site mutations, identifying a new potential therapeutic target in this disease.
Insights
Mutations causing MET exon 14 skipping are found in lung cancer. MET inhibitors like crizotinib show promise, offering a new treatment strategy for patients with this genetic alteration.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in MET exon 14 splice sites lead to exon skipping.
- This alteration results in a deletion of the CBL E3-ubiquitin ligase-binding site.
- The aberrant MET protein exhibits decreased turnover and is oncogenic in preclinical models.
Purpose of the Study:
- To investigate the therapeutic potential of MET inhibitors in lung adenocarcinoma with MET exon 14 skipping.
- To highlight a new therapeutic strategy for a specific subset of lung cancer patients.
Main Methods:
- Clinical observation of four patients with stage IV lung adenocarcinomas.
- Treatment with MET inhibitors crizotinib and cabozantinib.
Main Results:
- Patients with MET exon 14 skipping mutations responded to crizotinib and cabozantinib.
- These findings suggest a therapeutic benefit in this specific patient population.
Conclusions:
- Oncogenic MET exon 14 splice site mutations occur in approximately 4% of lung adenocarcinomas.
- MET inhibitors represent a potential targeted therapy for lung adenocarcinomas harboring these mutations.
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