Unveiling Mechanisms of Chemotherapy Resistance: Targeting FOXP1 Phase Separation in Small Cell Lung Cancer

Abstract Our study elucidates the role of FOXP1 in chemoresistance in SCLC. FOXP1 enhances chemoresistance by regulating SP8 expression through its super-enhancer (SP8-SE), with SP8 mediating resistance via the homologous recombination repair (HRR) pathway. We also discovered that FOXP1 forms punctate nuclear structures indicative of liquid-liquid phase separation ¹, crucial for its transcriptional regulation. Targeting the FOXP1-SP8-HR axis with BRD4 and PARP inhibitors showed synergistic effects in reducing tumor growth in vitro and in patient-derived xenograft models. These findings identify FOXP1 as a critical mediator and marker of chemoresistance in SCLC, providing a foundation for developing targeted therapies to overcome this resistance.