Abstract 6809: IFITM3/MET axis drives osimertinib resistance through Akt pathway activation in <i>EGFR</i>-mutant lung cancer

Abstract EGFR-mutant non-small-cell lung cancer (NSCLC) patients often experience significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these therapies inevitably emerges over time through various mechanisms, limiting the long-term effectiveness of the treatment. The mechanisms of resistance and the duration required for resistance to emerge are highly variable and difficult to predict, highlighting the need for new therapeutic strategies to suppress resistance. In this study, we elucidated the mechanism by which IFITM3, a membrane protein whose expression is upregulated by cytokine stimulation, contributes to reduced sensitivity to the EGFR-TKI osimertinib and promotes the development of resistance through Akt pathway activation. Additionally, we demonstrated that IFITM3 levels are elevated in pre-treatment clinical specimens from EGFR-mutant NSCLC patients who developed early resistance to osimertinib, supporting its role in resistance development. Furthermore, Combined treatment with osimertinib and MET inhibitor results in synergistic growth inhibition in NSCLC xenograft mouse models with high IFITM3 expression. These findings provide a rationale for clinical trials investigating the co-administration of MET and EGFR inhibitors in patients with elevated IFITM3 levels to address the heterogeneity of EGFR-TKI resistance mechanisms. Citation Format: Ritsu Ibusuki, Eiji Iwama, Atsushi Shimauchi, Hiroyuki Inoue, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Isamu Okamoto. IFITM3/MET axis drives osimertinib resistance through Akt pathway activation in EGFR-mutant lung cancer [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 6809.