BMP4-driven morphogenetic reprogramming sustains EGFR-TKI resistance via SOX2 suppression and EMT activation

Drug-resistant cells pose a major challenge to targeted therapy in EGFR-mutant lung adenocarcinoma (LUAD), yet the survival pathways they depend on remain unclear. Here, we identify BMP4 signaling as a key driver of resistance and therapeutic persistence. BMP4 is selectively enriched in EGFR-TKI-selected resistant cells, where it suppresses SOX2 and promotes an epithelial-mesenchymal transition (EMT)-like state. Knockdown of BMP4 or its receptor BMPR2 triggered apoptosis, upregulated pro-apoptotic factors (BAD, BMF), and impaired colony formation. Pharmacologic or inducible inhibition of BMP4 sensitized resistant cells, as well as residual tolerant populations in EGFR-TKI-sensitive cells, to osimertinib, while BMP4 enrichment also conferred cisplatin tolerance. Mechanistically, TGF-β1 induced BMP4 expression, and HDAC1/2 inhibition de-repressed BMP4, establishing a cytokine-epigenetic axis that maintains the BMP4^high/SOX2^low phenotype. Clinical analyses further revealed that BMP4 expression correlates with EMT signatures, chemoresistance pathways, and poor patient survival. These findings define a developmental signaling network in which BMP4 suppresses SOX2 to promote EMT, sustain resistant cell survival, and drive therapeutic resistance. Targeting the BMP4 axis presents a promising strategy for overcoming resistance in EGFR-mutant LUAD.