Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET Exon 14 splicing alternations
Introduction
Lung cancer is the leading cause of cancer-related death worldwide, and in recent years, we have witnessed the development of targeted therapies against many of the molecules frequently mutated in lung cancer [1]. In fact, two-thirds of lung adenocarcinoma cases harbor driving mutations that activate the receptor tyrosine kinases (for example, EGFR and less frequently, ALK, ROS1, RET, MET and HER2) and/or their downstream pathways, such molecules that play key roles in the RAS-RAF-MEK-ERK pathway and the PI3K-AKT pathway) [2], [3], [4]. Recently, advancement in next-generation sequencing (NGS) technology has greatly assisted the discovery of rarer driver mutations that may serve as potential therapeutic targets in lung cancer. MET has been identified as a novel promising target. Recently, the discovery of MET exon 14 skipping further attracts attention on MET-targeting therapies. It is reported that NSCLC patients harboring MET exon 14 mutation responded effectively to MET inhibitors such as crizotinib [5], [6], [7], [8], [9], [10], [11], [12].
Although emerging the encouraging clinical data about MET, experience on other RTK inhibitors suggests that resistance will develop despite remarkable initial responses [13], [14]. The known mechanisms of acquired resistance to kinase inhibitors can been classified into following categories: secondary mutations; gene amplification; bypass or alternative signaling activation; and histological and phenotypic transformation among others [15]. However, the prevalence of mechanisms of resistance to MET inhibitors among patients with MET exon 14 skipping remains unknown.
Through targeted NGS with a selected cancer-related gene panel, we identified one such MET exon 14 splicing mutation in a Chinese patient with lung adenocarcinoma, who responded to crizotinib. Several acquired mutations in the MET kinase domain, such as D1228N/H and Y1230H, were found at time of progression on crizotinib.
Section snippets
Case presentation
A 60-year-old Chinese woman having no-smoking history was admitted to our hospital. She was diagnosed with stage IV left lung adenocarcinoma in January 2015, with a 5.7 × 5.1 cm left pleural-based mass invading the fourth rib, left hilar lymphadenopathy, and numerous bilateral sub-centimeter pulmonary nodules, (confirmed by biopsy). Initial genotyping of his lung tumor by a mass spectrometry–based multiplex PCR assay for common lung cancer mutations, sizing assays for EGFR, and an ALK fluorescence
Discussion
We demonstrated a patient with lung adenocarcinoma and MET exon 14 splicing mutation that was responsed to crizotinib and developed acquired resistance to crizotinib. The second peripheral blood genetic testing at the time of progression showed acquired mutations in the MET kinase domain, D1228N/H and Y1230H; in addition to the original MET splice site mutation.
Somatic splicing alternations flanking exon 14 of MET occur in 4% of lung adenocarcinomas, based on recently whole exome sequencing
Conflict of interest and source funding
The authors declared no conflicts of interests.
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These authors contributed equally to this work.