Abstract 4714: Elucidating mechanisms of acquired resistance to mobocertinib in non-small cell lung cancer harboring EGFR exon 20 insertion mutations

Mobocertinib (TAK-788) is an oral irreversible tyrosine kinase inhibitor specifically developed to target EGFR exon 20 insertion (ex20ins) mutant non-small cell lung cancer (NSCLC); however, acquired resistance inevitably develops, limiting its clinical efficacy. This study aims to elucidate mechanisms of mobocertinib resistance through multiple clinical and preclinical approaches. Through targeted Next-Generation Sequencing on tumor samples from a patient with EGFR ex20ins (A767_S768insSVD) mutant NSCLC treated with mobocertinib, we identified secondary KRAS Q61H mutation as a potential resistance mechanism. To recapitulate clinical resistance, we successfully established a cell line (TH937) derived from this patient's pre-treatment tumor. In vivo mobocertinib-resistant tumors (mobo-R) were generated by continuous oral administration of mobocertinib to TH937 xenograft nude mice. Although no actionable secondary EGFR or KRAS mutations were identified in whole exome sequencing, transcriptomic analyses revealed upregulation of MAPK and RAS-related signaling in mobo-R tumors. In vitro analyses also showed reactivation of ERK signaling after mobocertinib treatment, while phosphorylation of 49 major receptor tyrosine kinases (RTKs), including EGFR and other ErbB family members, was not observed. These finding indicates that RTK-independent MAPK reactivation, potentially driven by RAS signaling, may serve as a resistance mechanism. In conclusion, we found that genomic or transcriptomic alterations of MAPK/RAS signaling mediate mobocertinib resistance. Further validation and exploration are needed to improve the therapy of EGFR ex20insmutant NSCLC. Citation Format: Gaku Yamamoto, Yu Tanaka, Yoshitaka Zenke, Jie Liu, Tetsuya Sakai, Hiroki Izumi, Eri Sugiyama, Shigeki Umemura, Shingo Matsumoto, Kiyotaka Yoh, Koichi Goto, Susumu S. Kobayashi, Hibiki Udagawa. Elucidating mechanisms of acquired resistance to mobocertinib in non-small cell lung cancer harboring EGFR exon 20 insertion mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4714.