Targeting FGFR in non-small cell lung cancer: implications from the landscape of clinically actionable aberrations of FGFR kinases
Zhen Zhou, Zichuan Liu, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang Shao, Hongyan Liu, Yang Yu
Abstract
<h3>Objective:</h3> Dysfunction in fibroblast growth factor receptor (FGFR) signaling has been reported in diverse cancer types, including non-small cell lung cancer (NSCLC). The frequency of <i>FGFR</i> aberrations in Chinese NSCLC patients is therefore of great clinical significance. <h3>Methods:</h3> A total of 10,966 NSCLC patients whose tumor specimen and/or circulating cell-free DNA (cfDNA) underwent hybridization capture-based next-generation sequencing were reviewed. Patients’ clinical characteristics and treatment histories were also evaluated. <h3>Results:</h3> <i>FGFR</i> aberrations, including mutations, fusions, and gene amplifications, were detected in 1.9% (210/10,966) of the population. <i>FGFR</i> abnormalities were more frequently observed in lung squamous cell carcinomas (6.8%, 65/954) than lung adenocarcinomas (1.3%, 128/9,596). <i>FGFR</i> oncogenic mutations were identified in 19 patients (∼0.17%), of which, 68% were male lung squamous cell carcinoma patients. Eleven out of the 19 patients (58%) had concurrent altered PI3K signaling, thus highlighting a potential combination therapeutic strategy of dual-targeting FGFR and PI3K signaling in such patients. Furthermore, <i>FGFR</i> fusions retaining the intact kinase domain were identified in 12 patients (0.11%), including 9 <i>FGFR3-TACC3</i>, 1 <i>FGFR2-INA</i>, 1 novel <i>FGFR4-RAPGEFL1</i>, and 1 novel fusion between the <i>FGFR1</i> and <i>SLC20A2</i> 5′-untranslated regions, which may have caused <i>FGFR1</i> overexpressions. Concomitant <i>EGFR</i> mutations or amplifications were observed in 6 patients, and 4 patients received anti-EGFR inhibitors, in whom <i>FGFR</i> fusions may have mediated resistance to anti-EGFR therapies. <i>FGFR</i> amplification was detected in 24 patients, with the majority being <i>FGFR1</i> amplifications. Importantly, <i>FGFR</i> oncogenic mutations, fusions, and gene amplifications were almost always mutually exclusive events. <h3>Conclusions:</h3> We report the prevalence of <i>FGFR</i> anomalies in a large NSCLC population, including mutations, gene amplifications, and novel <i>FGFR</i> fusions.