A novel acquired EGFR-SEPT14 fusion confers differential drug resistance to EGFR inhibitors in lung adenocarcinoma: a rare EGFR alteration report

Abstract Backgrounds: The rapid development of comprehensive genomic profiling facilitates the identification of rare epidermal growth factor receptor (EGFR) mutations; however, the clinical implications of these newly identified rare mutations were largely unknown. Methods: A lung adenocarcinoma patient with leptomeningeal metastasis (LM) who was treated with various EGFR tyrosine kinase inhibitors (TKIs) was included in the study. Next-generation sequencing of 139 cancer-relevant genes was performed on the serial cerebrospinal fluid (CSF) specimens collected during the treatment. Simulated structural analysis and in vitro drug sensitivity were conducted to elucidate novel EGFR TKI resistant mechanisms. Results: The patient was initially positive for EGFR 19-exon deletion (19-Del), and upon drug resistance to first-generation EGFR inhibitors and osimertinib, a previously unreported EGFR-SEPT14 (E25:S7) fusion was identified. The patient achieved a promising response after treating intrathecal pemetrexed plus second-generation EGFR inhibitors. Structural analysis suggested that the fusion protein and wild-type EGFR had similar secondary structures but distinct tertiary structures. In vitro studies demonstrated that EGFR-SEPT14 fusion itself was not oncogenic; however, it could function together with EGFR 19-Del to confer drug resistance to first-generation inhibitors and osimertinib while remaining sensitive to some second- and third-generation EGFR inhibitors. Conclusions: Overall, this is the first study reporting EGFR fusions can serve as an acquired resistant mechanism to EGRR inhibitors in lung adenocarcinoma, which is potentially through heterodimerization with classic EGFR mutations, and the identification of its differential sensitivity to certain EGFR TKIs could facilitate personalized treatments to patients with rare EGFR alterations.