Overview: A cytokine-driven route to osimertinib resistance in EGFR-mutant NSCLC
Osimertinib has transformed treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) but resistance remains a critical hurdle. A combination of clinical data, tumor profiling, and functional studies now implicates IFITM3, a small antiviral membrane protein, in mediating resistance. The key finding is that IFITM3 interacts with the MET receptor to sustain AKT signaling, allowing cancer cells to survive despite EGFR blockade. This pathway links inflammatory cues in the tumor microenvironment (TME) with a durable resistance mechanism, opening new avenues for preventing or overcoming resistance in treatment-naïve patients as well as those with acquired resistance.
Clinical data link high IFITM3 to poor osimertinib response
A multi-institutional cohort of 127 patients with EGFR-mutant NSCLC treated with first-line osimertinib was analyzed. Researchers stratified patients by progression-free survival (PFS): 20 months (long). In the discovery phase, RNA-seq of 32 tumor samples identified IFITM3 as the sole gene significantly upregulated in short-PFS cases compared with long-PFS cases among over 19,000 genes analyzed. Validation in the remaining 95 pretreatment specimens showed that tumors with IFITM3 positivity (using a 10% cutoff for IFITM3-positive tumor cells) had a markedly shorter PFS (median 18.4 vs 24.8 months) and worse response rates. This points to IFITM3 expression as a potential biomarker for poorer osimertinib efficacy in EGFR-mutant NSCLC.
IFITM3 expression induced by osimertinib via cytokine signaling
Spatial transcriptomics and supporting experiments revealed that IFITM3 expression in tumor cells rises after osimertinib exposure, driven by inflammatory cytokines such as TNF-α, IL-6, and IFN-γ produced by tumor-adjacent cells and, in some cases, by the tumor cells themselves. RT-qPCR and immunofluorescence confirmed cytokine- and osimertinib-induced IFITM3 upregulation, with membrane-localized IFITM3 observed in treated cells. Blocking IL-6R or TNF-α tempered this induction, suggesting a cytokine-dependent mechanism by which OSI treatment can inadvertently nurture a resistant cell population through IFITM3 upregulation.
IFITM3 activates the PI3K-AKT axis via MET
Functional studies in EGFR-mutant NSCLC cell lines demonstrated that IFITM3 enhancement promotes persistent AKT phosphorylation, even when osimertinib is present. Reducing IFITM3 levels decreased AKT activation and mitigated resistance; conversely, forced IFITM3 expression conferred resistance. Notably, AKT inhibition (MK-2206) restored osimertinib sensitivity in IFITM3-overexpressing cells, underscoring PI3K-AKT as a downstream effector of the IFITM3-MET interaction.
Mechanistic insights: MET as a binding partner
Co-immunoprecipitation and proximity ligation assays revealed that IFITM3 binds MET, a receptor tyrosine kinase frequently implicated in EGFR-TKI resistance. Overexpression of IFITM3 increased MET phosphorylation and AKT signaling; IFITM3 knockdown dampened MET and AKT activity. Perturbing MET with capmatinib re-sensitized IFITM3-overexpressing cells to osimertinib, while lipid raft disruption with methyl-β-cyclodextrin attenuated MET activation, hinting at a raft-anchored signaling complex in which IFITM3 acts as a scaffold to amplify MET-PI3K-AKT signaling.
In vivo validation and therapeutic implications
In a xenograft model, tumors overexpressing IFITM3 resisted osimertinib, but concurrent MET inhibition with capmatinib restored sensitivity and suppressed tumor growth. These findings suggest that combining EGFR-TKIs with MET inhibitors could prevent or overcome IFITM3-driven resistance, addressing both primary and acquired resistance scenarios. The study also notes potential synergy with dual EGFR-MET targeting approaches, such as amivantamab, which has shown clinical benefit when added to EGFR-TKI therapy in EGFR-mutant NSCLC.
Clinical and research considerations
While the data illuminate a compelling resistance mechanism, several limitations warrant attention. The TME-tumor interactions observed in tissue analyses were not validated in live humanized or organoid models. The sample size for matched pretreatment and posttreatment specimens was limited, and additional large-scale studies are needed to ascertain how frequently IFITM3 upregulation drives resistance and whether it co-occurs with known genetic resistance mechanisms. Future work should explore strategies to prevent IFITM3 induction or to block the IFITM3-MET-AKT axis in treatment-naïve patients and in those who develop resistance to EGFR-TKIs.
Conclusion
The IFITM3-MET interaction provides a plausible, druggable route to osimertinib resistance in EGFR-mutant NSCLC by sustaining AKT signaling through MET. Targeting MET, or disrupting IFITM3’s raft-associated scaffolding, offers a rational strategy to enhance EGFR-TKI durability and improve patient outcomes in this challenging disease setting.
