Alterations in AR-FOXA1 signaling in prostate cancer progression and therapeutic resistance

The androgen receptor (AR) is instrumental in the onset and progression of prostate cancer (PCa), establishing androgen deprivation therapy (ADT) as the first-line treatment for metastatic disease. However, the effectiveness of ADT is commonly short-lived. Many patients eventually relapse and develop castration-resistant prostate cancer (CRPC), commonly marked by reactivated AR signaling. Although next-generation AR signaling inhibitors (ARSi) provide temporary control, resistance inevitably emerges. While a small subset of CRPC cases may evolve through AR-independent pathways, most regain partial AR function through multiple mechanisms. A key regulator of AR activity is the pioneer transcription factor FOXA1, which governs AR binding to chromatin. The AR-FOXA1 axis is essential for prostate luminal epithelial cell lineage determination and drives the development of prostate adenocarcinoma. Emerging evidence shows profound alterations in this axis in CRPC and in tumors resistant to ARSi therapies. In this review, we highlight the genetic, epigenetic, transcriptional, and posttranscriptional changes within the AR-FOXA1 axis in PCa following ADT and ARSi treatments.