Overview: A New Mechanism Behind Osimertinib Resistance in EGFR-Mutant NSCLC
Osimertinib has transformed the treatment landscape for patients with EGFR-mutant non-small cell lung cancer (NSCLC). Yet resistance remains a major hurdle. A recent study identifies a non-genetic mechanism: the membrane protein IFITM3 interacts with MET to activate the PI3K-AKT signaling axis, enabling tumor cells to survive despite EGFR blockade. This discovery offers a potential path to delay or overcome resistance by combining osimertinib with MET inhibitors or strategies that disrupt IFITM3’s function in lipid rafts.
Clinical Context: From Patient Cohorts to Molecular Clues
Researchers analyzed 127 patients with EGFR-mutant NSCLC who received osimertinib as first-line therapy across eight institutions. They conducted RNA sequencing on a discovery group (32 samples) to identify genes linked to short (20 months) progression-free survival (PFS). IFITM3 emerged as the sole significantly upregulated gene in the short-PFS group. To validate these findings, the team performed immunohistochemistry (IHC) for IFITM3 on 95 pretreatment specimens and corroborated a consistent association between high IFITM3 expression and poorer osimertinib response. In a separate analysis, post-treatment specimens showed higher IFITM3 levels, suggesting osimertinib itself may drive IFITM3 upregulation in tumor cells via cytokine signaling.
IFITM3 and Cytokine-Driven Upregulation
Spatial transcriptomics and RT-qPCR revealed that inflammatory cytokines—TNF-α, IL-6, and IFN-γ—peaked after osimertinib exposure and correlated with increased IFITM3 in tumor cells and the surrounding tumor microenvironment (TME). Blocking IL-6R or TNF-α attenuated the osimertinib-induced rise in IFITM3, indicating cytokine-driven regulation rather than EGFR blockade alone. These findings highlight a dynamic TME–tumor cell crosstalk that fosters resistance by boosting IFITM3, which in turn fuels survival signaling.
The IFITM3–MET–AKT Axis: A Driver of Resistance
Central to the resistance mechanism is IFITM3’s interaction with MET. Co-immunoprecipitation and proximity ligation assays demonstrated that IFITM3 binds MET, leading to sustained AKT phosphorylation even in the presence of osimertinib. Knocking down IFITM3 reduced MET and AKT activation, while overexpressing IFITM3 increased resistance. Importantly, inhibiting AKT or MET restored osimertinib sensitivity in IFITM3-overexpressing cells, underscoring a MET–AKT dependency for the resistance phenotype.
Lipid Rafts and Therapeutic Implications
Further experiments implicated lipid rafts in this resistance mechanism. Disrupting lipid rafts with methyl-β-cyclodextrin diminished MET activation and reinstated sensitivity to osimertinib, suggesting IFITM3 acts as a raft-associated scaffold facilitating MET–PI3K–AKT signaling. Pharmacologic MET inhibition (capmatinib) reversed resistance in cell lines and, in xenograft models, combining osimertinib with capmatinib prevented tumor growth, indicating a feasible strategy to forestall resistance in patients starting EGFR-TKI therapy.
Clinical and Translational Outlook
The study’s translational promise lies in identifying patients who may benefit from upfront combination therapy. Given the heterogeneity of IFITM3 expression within tumors, a biomarker-driven approach could tailor decisions about adding MET inhibitors to EGFR-TKI regimens. While these data are compelling, the authors acknowledge limitations, including the lack of in vivo validation for TME–tumor interactions and the need for larger matched patient cohorts to confirm IFITM3’s predictive value and its relation to known resistance mechanisms.
Takeaway
IFITM3 upregulation—driven by cytokines in the TME and cancer cells themselves—activates MET-AKT signaling to sustain NSCLC cells under osimertinib pressure. Targeting the MET axis, potentially in combination with EGFR-TKIs from the outset, may delay resistance and extend disease control for patients with EGFR-mutant NSCLC.
