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

Ritsu Ibusuki¹, Eiji Iwama², Atsushi Shimauchi¹

¹Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Molecular Cancer

|October 29, 2025

Abstract

Background:

Despite 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.

Methods:

To 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.

Results:

Transcriptomics 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.

Conclusions:

Our 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.

Insights

Interferon-induced transmembrane protein 3 (IFITM3) upregulation, driven by the tumor microenvironment, causes osimertinib resistance in non-small cell lung cancer (NSCLC). Targeting the IFITM3-MET pathway may improve treatment outcomes for NSCLC patients.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Acquired resistance to osimertinib is a significant challenge in treating EGFR-mutant non-small cell lung cancer (NSCLC).
While genetic resistance mechanisms are known, the molecular drivers of resistance induction remain unclear.

Purpose of the Study:

To identify molecular mediators that induce osimertinib resistance in EGFR-mutant NSCLC.
To elucidate the mechanism by which these mediators confer resistance.
To explore potential therapeutic strategies targeting these mediators.

Main Methods:

Analysis of clinical NSCLC samples and cell lines using transcriptomics, spatial transcriptomics, and proteomics.
Investigated the role of IFITM3 in osimertinib resistance via cell viability assays, immunofluorescence, and quantitative PCR.
Utilized mouse xenograft models to assess therapeutic interventions.

Main Results:

Upregulation of interferon-induced transmembrane protein 3 (IFITM3) in pretreatment NSCLC specimens correlated with poor response to osimertinib.
IFITM3 expression increased due to tumor microenvironment cytokines during osimertinib treatment.
IFITM3 promoted osimertinib resistance by interacting with MET and activating AKT signaling, which was reversed by MET inhibition in vivo.

Conclusions:

Upregulation of IFITM3 by tumor microenvironment cytokines is a novel mechanism of osimertinib resistance in NSCLC.
Targeting the IFITM3-MET axis presents a potential strategy to overcome osimertinib resistance and improve treatment outcomes for EGFR-mutant NSCLC.

Read full analysis

Keywords:

EGFR-mutant non–small cell lung cancer Drug resistance EGFR-TKI IFITM3 Osimertinib

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