Abstract 958: Novel syngeneic models for evaluating therapies targeting EGFRL858R/T790Mand EGFRL858R/T790M/C979Sresistance mutations in NSCLC

Abstract Both the first and second-generation EGFR-TKIs drugs have markedly improved the survival of NSCLC patients with activating EGFR mutations. However a secondary T790M mutation rapidly drives resistance towards these drugs. Third-generation EGFR-TKIs potently suppress the T790M mutant, but the subsequent C797S mutation abolishes their covalent binding, leaving no currently approved targeted options. Therefore, our laboratory generated conditional knock-in C57BL/6 mice harboring human EGFRL858R/T790M or EGFRL858R/T790M/C979S, which quickly develop spontaneous NSCLC and yield primary tumor cell lines.In syngeneic, immune-competent C57BL/6 hosts, the fourth-generation TKI under research, BLU-945, markedly inhibited both EGFRL858R/T790M and EGFRL858R/T790M/C979S tumor growth. In contrast, osimertinib was effective only against EGFRL858R/T790M, but failing against the EGFRL858R/T790M/C979S mutation. This demonstrates how our novel mouse models faithfully recapitulate and allow the reversal of osimertinib resistance in vivo. Citation Format: Lei Ci, Kai Zhou, Jiangyan Liu, Ruilin Sun. Novel syngeneic models for evaluating therapies targeting EGFRL858R/T790Mand EGFRL858R/T790M/C979Sresistance mutations in NSCLC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 958.