IGF2R as a master regulator of acquired EGFR inhibitor resistance and therapeutic target in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), a leading cause of cancer-related mortality worldwide, often develops resistance to targeted therapies, limiting long-term treatment success. Although agents such as the EGFR inhibitor osimertinib and the marine-derived small molecular compound Debromoaplysiatoxin (DAT), which we have demonstrated to markedly inhibit EGFR signaling in our preliminary data, show efficacy in advanced NSCLC, acquired resistance remains a major clinical challenge. This study identifies insulin-like growth factor 2 receptor (IGF2R) as a key mediator of acquired resistance to both osimertinib and DAT. IGF2R was significantly upregulated in resistant NSCLC cells. Stable knockdown of IGF2R suppressed proliferation, migration, and invasion; induced cell-cycle arrest and apoptosis; and resensitized resistant cells to osimertinib and DAT in vitro and in vivo. Mechanistically, in osimertinib-resistant models, IGF2R interacted with IGF1R to suppress RAF/MAPK and PI3K/AKT/mTOR signaling pathways; in DAT-resistant models, IGF2R exerted its inhibitory effect through interaction with EGFR. Furthermore, silencing IGF2R suppressed epithelial-mesenchymal transition and impaired DNA damage repair pathways. These findings establish IGF2R as a central regulator of acquired drug resistance in NSCLC and highlight IGF2R targeting as a promising strategy to overcome resistance and improve outcomes in refractory NSCLC.