Responses to the multitargeted MET/ALK/ROS1 inhibitor crizotinib and co-occurring mutations in lung adenocarcinomas with MET amplification or MET exon 14 skipping mutation

Abstract

Introduction Genomic aberrations involving ALK, ROS1 and MET can be driver oncogenes in lung adenocarcinomas. Identification of tyrosine kinase inhibitors (TKIs) with activity against these tumors and of preclinical systems to model response are warranted. Methods We analyzed cases with lung adenocarcinomas for representative genomic aberrations, evaluated the response to the multitargeted MET/ALK/ROS1 crizotinib TKI in cases with MET aberrations and profiled lung cancer cell lines with the aforementioned genomic changes. Results Lung cancer cell lines with ALK rearrangement, ROS1 rearrangement or MET amplification had expected in vitro responses to crizotinib and the ALK/ROS1 TKI ceritinib. However, a commercially-available cell line with MET exon 14 skipping mutation and co-occurring PIK3CA-p.Glu545Lys mutation did not respond to crizotinib; suggesting the latter abrogated response. 10% of MET exon 14 skipping mutation co-occurred with PIK3CA mutation in the TCGA cohort. Putative crizotinib-responsive somatic mutations (ALK rearrangements, ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) were present in 10% of lung adenocarcinomas analyzed at our service and in 9.5% of the TCGA lung adenocarcinoma database. One patient each whose advanced tumors harbored high level MET amplification with wild-type PIK3CA or MET exon 14 skipping mutation with PIK3CA-p. Glu542Lys had significant responses to crizotinib; suggesting that PIK3CA co-mutation did not affect clinical response. Conclusions Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to MET TKIs in human lung adenocarcinomas but co-occurrence of PIK3CA mutation needs to be better evaluated as a modifier of response to TKI therapy. MET TKIs should not be omitted from MET exon 14 skipping mutated tumors until further preclinical and clinical data can confirm or refute mechanisms of primary or acquired resistance to crizotinib and other MET TKIs in these recalcitrant cancers.

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

“…In another recent study, lung adenocarcinoma cell lines with ALK rearrangement, ROS1 rearrangement or MET amplification showed in vitro response to crizotinib and ceritinib (an ALK/ROS1 inhibitor) (30). The evaluation of a cohort of patients affected by lung adenocarcinoma performed in the same analysis revealed that putative genomic aberrations potentially targetable by crizotinib (ALK and ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) are present in the 10% of cases.…”

“…The evaluation of a cohort of patients affected by lung adenocarcinoma performed in the same analysis revealed that putative genomic aberrations potentially targetable by crizotinib (ALK and ROS1 rearrangements, high level MET amplification or MET exon 14 skipping mutations) are present in the 10% of cases. MET exon 14 skipping mutation was reported to predict response to anti-Met tyrosine kinase inhibitor (TKI) in lung adenocarcinomas (30).…”

MET in human cancer: germline and somatic mutations

“…The incidence of MET mutations in lung cancers is 3% in squamous cell lung cancers, 5.6% in NSCLC, and 8% in lung adenocarcinomas (29)(30)(31). The implications of MET JM domain mutations and receptor regulation on the clinical outcome of lung cancer patients have become evident in recent years (32)(33)(34)(35)(36)(37). Moreover, the importance of these Sema and JM domain mutations is not limited to lung cancer.…”

Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models

“…Most METex14 del mutations have been identified in lung adenocarcinoma, adenosquamous, or pulmonary sarcomatoid carcinoma subtypes, collectively comprise approximately 3% of non-small cell lung cancer (NSCLC), and are statistically exclusive with other known oncogenic drivers (4,8,9). Genetic, pharmacologic, and clinical studies have further established that this collection of mutations exhibit the characteristics of driver oncogenes and that MET inhibitors are clinically active in NSCLC patients with these mutations (8)(9)(10)(11)(12)(13).…”