This study reveals the critical role of IFITM3 in conferring resistance to the EGFR-TKI osimertinib in EGFR-mutant NSCLC. Through multiple experimental approaches, the authors demonstrate that IFITM3 binds to MET and activates the AKT pathway, promoting drug resistance. They further show that combining MET inhibitors effectively overcomes this resistance mechanism, providing a novel strategy for clinical intervention.
Literature Overview
The article titled 'IFITM3-MET interaction mediates osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer' published in Molecular Cancer summarizes resistance mechanisms to osimertinib in EGFR-mutant NSCLC. Through transcriptomic profiling, immunohistochemistry, spatial transcriptomic analysis, and multiple molecular/cellular experiments, the study identifies significant IFITM3 overexpression in resistant patients, regulated by tumor microenvironment (TME) cytokines. Further experiments reveal IFITM3 binds MET to activate the AKT signaling pathway, reducing osimertinib efficacy, while MET inhibitors effectively reverse this resistance.
Background Knowledge
EGFR mutations represent common oncogenic drivers in NSCLC, accounting for ~40% of Asian populations. Although third-generation EGFR-TKI osimertinib shows remarkable initial responses, approximately 50% of patients develop resistance within 19 months. Known resistance mechanisms include EGFR secondary mutations and MET amplification, but nearly half of cases remain mechanistically undefined, suggesting widespread non-genetic resistance mechanisms. IFITM3, an interferon-induced transmembrane protein involved in antiviral defense and cell signaling, has not been previously linked to tumor drug resistance. This study establishes its novel role in EGFR-TKI resistance and proposes MET targeting as a therapeutic strategy, providing theoretical foundations for future research and clinical applications.
Research Methods and Experiments
The research team conducted transcriptomic profiling and immunohistochemical validation using clinical samples from 127 EGFR-mutant NSCLC patients receiving first-line osimertinib therapy, categorizing them as short-term (<12 months) or long-term (>20 months) progression-free survival (PFS) responders. Spatial transcriptomic analyses characterized tumor cell-microenvironment interactions and cytokine expression patterns. Functional validation employed IFITM3 knockdown/overexpression models in PC-9 and H1975 cells, combined with osimertinib resistance induction systems, proteomic profiling, co-immunoprecipitation, and proximity ligation assays to confirm IFITM3-MET interactions. Finally, xenografted mouse models evaluated MET inhibitor intervention effects on drug resistance.
Key Conclusions and Perspectives
Research Significance and Prospects
This work establishes IFITM3's novel functional role in EGFR-TKI resistance, demonstrating its potential as a biomarker and therapeutic target. Future studies should explore clinical correlations between IFITM3 expression levels and resistance progression, while evaluating therapeutic efficacy of IFITM3-MET pathway inhibitors. These findings offer new strategies to overcome resistance in EGFR-mutant lung cancer.
Conclusion
This systematic investigation identifies IFITM3-MET interaction as a novel resistance mechanism in EGFR-mutant NSCLC through AKT pathway activation. The process is cytokine-regulated within the tumor microenvironment, and animal models demonstrate MET inhibitors can restore osimertinib sensitivity in resistant cells. The study provides clinical insights into biomarker development and combination therapies that may improve long-term outcomes for third-generation EGFR-TKI treatments.
