ArticleMolecular cancer2025
IFITM3-MET interaction drives osimertinib resistance through AKT pathway activation in EGFR-mutant non-small cell lung cancer.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Efficacy and safety of bispecific antibodies versus other antitumor therapies in solid tumors: a systematic review and meta-analysis.Frontiers in immunology · 2026Pooled it
- Interferon-induced transmembrane (IFITM) proteins at the tumour-immune interface: A four-axis framework for their context-dependent roles.Clinical and translational medicine · 2026Review
- Interferon-induced transmembrane proteins in cancer and virus biology: a membrane perspective.mBio · 2026Review
- Association of TP53 gain-of-function mutations with early osimertinib resistance in epidermal growth factor receptor-mutant lung adenocarcinoma.ESMO open · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Bidirectional coupling among EMT, AXL-RB1 signaling and lineage switch drives resistance to osimertinib and worse clinical outcomes in NSCLC.bioRxiv : the preprint server for biology · 2026Article
- Targeting ABCA3 impedes tumor progression and EGFR-TKI resistance in EGFR-mutant LUAD.Cancer cell international · 2026Article
- Immunosuppressive cells as barriers to cancer therapy: mechanisms and emerging solutions.Frontiers in immunology · 2026Review
- Targeted nanoparticle-mediated Co-delivery of IFITM3 KO and ponatinib reverses TKI resistance in chronic myeloid leukemia.Frontiers in pharmacology · 2026Article
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23 authors.
Funding
Abstract
backgroundDespite an initial favorable response of EGFR-mutant non-small cell lung cancer (NSCLC) to osimertinib, an EGFR tyrosine kinase inhibitor (TKI), resistance to this drug inevitably develops. Whereas genetic mechanisms for such acquired resistance have been identified, the molecular mediators of resistance induction have remained unclear.
methodsTo identify factors that mediate induction of osimertinib resistance, we studied clinical samples from individuals with EGFR-mutant NSCLC as well as cell lines including PC-9 and H1975. Methods adopted included transcriptomics analysis and immunohistochemistry of pretreatment NSCLC specimens, spatial transcriptomics analysis, a cell viability assay, immunofluorescence and quantitative PCR analysis, RNA sequencing, immunoblot analysis, comprehensive proteomics analysis by mass spectrometry, co-immunoprecipitation and proximity ligation assays, and a mouse xenograft tumor model.
resultsTranscriptomics analysis of pretreatment clinical specimens identified IFITM3 (interferon-induced transmembrane protein 3) as a gene specifically upregulated in patients with a poor response to osimertinib treatment. Immunohistochemistry confirmed that patients with IFITM3-positive tumors experienced a shorter progression-free survival on osimertinib treatment. Spatial transcriptomics and other analyses further revealed that IFITM3 expression in tumor cells 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 in NSCLC cell lines through interaction with MET and activation of the AKT signaling pathway. Furthermore, combined treatment with a MET inhibitor suppressed the development of osimertinib resistance in a mouse xenograft tumor model.
conclusionsOur findings reveal that upregulation of IFITM3 driven by TME cytokines represents a previously unrecognized mechanism of osimertinib resistance, and they suggest that targeting of the IFITM3-MET axis may improve EGFR-TKI treatment outcome for EGFR-mutant NSCLC.
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