Abstract 5556: Development of osimertinib resistant mouse models for preclinical evaluation of third-generation EFGR-TKI therapies

Abstract Osimertinib was developed as a third-generation EGFR tyrosine kinase inhibitor. Numerous clinical trials have demonstrated that EGFR-TKI targeted drug therapy for non-small cell lung cancer can prolong the survival of patients. However, its efficacy is impacted by acquired EGFR C797 mutations (including EGFR triple mutations Del19/T790M/C797S and L858R/T790M/C797S). To better understand the drug resistance mechanism towards Osimertinib, we have developed both in vitro and in vivo models associated with Osimertinib resistance for the evaluation of novel therapeutics that overcome Osimertinib resistance. The human lung adenocarcinoma H1975 is a cell line with double mutations in the EGFR gene (L858R/T790M). To create a model which mimics patients in clinic who received Osimertinib treatment and developed drug resistance thereafter, the C797S mutation was introduced using advanced gene editing technology for site-directed mutagenesis, resulting in the EGFR triple-mutant cell line (H1975 with EGFR L858R/T790M/C797S). To explore other Osimertinib resistance mechanisms than the C797 mutation, we induced cell lines in vitro with multiple rounds of increasing concentrations of Osimertinib. Following the induction of Osimertinib, the IC50 of different cell lines treated by Osimertinib was assessed, confirming increased resistance to Osimertinib. In vivo tumorigenicity and efficacy studies with Osimertinib were performed to screen and validate our Osimertinib-resistant models. Currently, we have obtained the EGFR triple mutant H1975 and PC-14 cell lines that exhibit resistance to Osimertinib for in vitro and in vivo study, which serve as vital tools for studying drug resistance mechanisms and developing innovative treatment strategies. Citation Format: Hongyan Sun, Yinuo Wang, Shiying Guo, Jianming Xu, Xiang Gao, Jun Wang. Development of osimertinib resistant mouse models for preclinical evaluation of third-generation EFGR-TKI therapies [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 5556.