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

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. Overall design: We analyzed formalin-fixed, paraffin-embedded (FFPE) tumor sections and clinical data for 32 individuals with EGFR mutant NSCLC who received osimertinib monotherapy as a first-line treatment between January 2016 and April 2023 across eight institutions. We defined short and long PFS as <12 and >20 months, respectively, on the basis of the results of a previous clinical study of osimertinib treatment. RNA-seq analysis was performed for 32 patients with a short PFS (n = 10) or long PFS (n = 22) who had sufficient RNA available, with these individuals constituting the discovery cohort.