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

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Drug-resistant cells present a significant challenge in EGFR-mutant lung adenocarcinoma (LUAD) treatment.
• The specific survival pathways exploited by resistant cells remain largely unknown.

Purpose of the Study:

• To identify key survival pathways driving therapeutic resistance in EGFR-mutant LUAD.
• To investigate the role of BMP4 signaling in mediating resistance to EGFR-tyrosine kinase inhibitors (TKIs) and chemotherapy.

Main Methods:

• Investigated BMP4 signaling in EGFR-TKI-selected resistant LUAD cells.
• Utilized gene knockdown (BMP4, BMPR2) and pharmacologic inhibition of BMP4.
• Analyzed effects on apoptosis, cell proliferation, and response to osimertinib and cisplatin.
• Examined the regulatory axis involving TGF-β1, BMP4, SOX2, and epigenetic modifiers (HDAC1/2).
• Correlated BMP4 expression with clinical data, including EMT signatures and patient survival.

Main Results:

• BMP4 signaling is selectively enriched in resistant LUAD cells, suppressing SOX2 and promoting an epithelial-mesenchymal transition (EMT)-like state.
• BMP4 or BMPR2 knockdown induced apoptosis and impaired colony formation.
• BMP4 inhibition sensitized resistant cells and tolerant populations to osimertinib and conferred cisplatin tolerance.
• A cytokine-epigenetic axis (TGF-β1 and HDAC1/2 inhibition) maintains high BMP4 expression.
• Clinical analysis showed BMP4 expression correlates with EMT, chemoresistance, and poor patient survival.

Conclusions:

• BMP4 acts as a critical driver of therapeutic resistance in EGFR-mutant LUAD by suppressing SOX2 and promoting EMT.
• Targeting the BMP4 signaling axis offers a potential therapeutic strategy to overcome resistance to EGFR-TKIs and chemotherapy.
• The identified BMP4-SOX2-EMT axis provides a novel understanding of resistance mechanisms in LUAD.