Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping

Abstract

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.

Figure 1

Diagram of MET exon 14 alterations in relation to the 5’ and 3’ splice sites.

Figure 2

A. Baseline and 4 week PET scan from Patient 2 (MET c.3028G>C exon 14 splice variant) following treatment with cabozantinib. Imaging shows complete PET response by PERCIST criteria in the patient’s liver metastasis. B. Baseline and 4 week CT scan from Patient 4 (MET c.3024_3028delAGAAGGTATATT exon 14 splice variant) following treatment with crizotinib. Imaging shows a response in the patient’s lung tumor. C. Baseline and 6 week CT scan from Patient 5 (MET c.3028+1G>T exon 14 splice variant) following treatment with crizotinib. Imaging shows a response in the patient’s lung tumor. D. Baseline and 6 week CT scan from Patient 5 (MET c.3028+1G>T exon 14 splice variant) following treatment with crizotinib. Imaging shows a response in the patient’s liver metastasis. E. Baseline and 8 week CT scan from Patient 7 (MET c.3028G>T exon 14 splice variant) following treatment with crizotinib. Image shows a response in the patient’s lung tumors.