IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non–small cell lung cancer

Despite an initial favorable response of EGFR mutant non–small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance inevitably develops. We here performed transcriptomics analysis of pretreatment specimens and identified IFITM3 as a gene specifically upregulated in tumors that develop early resistance to osimertinib. Immunohistochemistry confirmed patients with IFITM3-positive tumors experienced a shorter progression-free survival. Spatial transcriptomics and other analyses further revealed that IFITM3 expression was increased in response to cytokines derived from the tumor microenvironment (TME) during osimertinib treatment. IFITM3 was found to promote the development of osimertinib resistance through interaction with MET and activation of the AKT pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse model. Our findings thus reveal that upregulation of IFITM3 represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting the IFITM3-MET axis may improve treatment outcomes.