Androgen receptor reactivation in castration-resistant prostate cancer: mechanisms, epigenetic adaptation, and therapeutic vulnerabilities.

Castration-resistant prostate cancer (CRPC) remains a difficult clinical problem, although androgen deprivation therapy and next-generation androgen receptor (AR) pathway inhibitors have greatly improved patient treatment. CRPC is not simply an androgen-independent disease. In many cases, tumor cells still depend on persistent or restored AR signaling under castrate conditions. AR reactivation is driven by several overlapping mechanisms, including AR amplification, AR overexpression, ligand-binding domain mutations, AR splice variants, intratumoral androgen synthesis, bypass signaling, and altered AR co-regulators. The AR axis is also connected with DNA damage repair. For example, PARP-1 can support both DNA repair and AR-driven transcription, which provides a rationale for combining AR-targeted therapy with PARP inhibition in selected patients. Epigenetic adaptation is another key layer in this process. Changes in chromatin accessibility, AR cistrome redistribution, pioneer factors, enhancer activity, and chromatin-modifying cofactors can reshape AR-dependent transcription. These changes help tumor cells maintain AR signaling and also promote heterogeneity, lineage plasticity, and more aggressive phenotypes. Recent single-cell transcriptomic and epigenomic studies further show that CRPC contains diverse resistant cell states, which may change during treatment. Importantly, these resistance mechanisms may also create therapeutic opportunities. Current and emerging strategies include AR degraders, AR N-terminal domain inhibitors, inhibitors of steroidogenesis and bypass pathways, PARP inhibitors, and epigenetic therapies targeting EZH2, BET proteins, p300/CBP, LSD1, or HDACs. Biomarker-guided treatment, including AR variants, DNA repair defects, ctDNA profiles, and chromatin states, may help select better therapies for CRPC patients.