Targeting FOXA1 with repurposed tigecycline to overcome therapeutic resistance in castration-resistant prostate cancer

Background Resistance to androgen receptor signaling inhibitors, including enzalutamide, remains a major obstacle in treating castration-resistant prostate cancer (CRPC). FOXA1, a pioneer transcription factor frequently overexpressed or mutated in prostate cancer, drives disease progression and represents a potential therapeutic target. Methods Through virtual screening, we identified tigecycline, an FDA-approved antibiotic, as a candidate compound that directly targets FOXA1. We assessed its effects on FOXA1 target gene expression and chromatin occupancy using chromatin immunoprecipitation assays in C4‑2 cells. The impact on FOXA1 mutation-driven progression was evaluated using C4‑2 cells stably expressing a FOXA1 point mutant. In vivo efficacy was examined in CRPC xenograft models. Results Tigecycline inhibited FOXA1 target gene expression and reduced FOXA1 chromatin occupancy. In FOXA1-mutant cells, tigecycline repressed mutant-driven gene expression, suppressed AR signaling activity, and decreased PSA levels, reversing the oncogenic effects driven by the mutant. Notably, tigecycline retained efficacy in FOXA1-mutant cell lines, likely through direct binding to FOXA1. In vivo, tigecycline suppressed CRPC tumor growth and reduced tumor PSA levels. Conclusion These findings support tigecycline as a potential therapeutic agent for CRPC by targeting FOXA1.