SAT-327 Targeting FOXA1-mediated Repression of TGF-B Signaling Supresses Castration-Resistant Prostate Cancer Progression

Prostate cancer (PCa) progressed to castration resistance (CRPC) is a fatal disease. CRPC tumors develop resistance to new-generation anti-androgen enzalutamide through lineage plasticity, characterized by epithelial-mesenchymal transition (EMT) and basal-like phenotype. FOXA1 is a transcription factor essential for epithelial lineage differentiation. Here, we demonstrate that FOXA1 loss leads to remarkable up-regulation of transforming growth factor beta 3 (TGFB3), which encodes a ligand of TGF-β pathway. Mechanistically, this is due to genomic occupancy of FOXA1 on an upstream enhancer of TGFB3 gene to directly inhibit its transcription. Functionally, FOXA1 down-regulation induces TGF-β signaling, EMT, and cell motility, which is effectively blocked by TGF-β receptor I inhibitor Galunisertib (LY2157299). Tissue microarray analysis confirmed reduced levels of FOXA1 protein and a concordant increase in TGF-β signaling, indicated by SMAD2 phosphorylation, in CRPC as compared to primary tumors. Importantly, combinatorial LY2157299 treatment sensitized PCa cells to enzalutamide, leading to synergistic effects in inhibiting cell invasion in vitro and xenograft CRPC tumor growth and metastasis in vivo. Therefore, our study establishes FOXA1 as an important regulator of lineage plasticity mediated in part by TGF-β signaling and supports a novel therapeutic strategy to control lineage switching and potentially extend clinical response to antiandrogen therapies. ­