Androgen Receptor Signalling in Prostate Cancer: Mechanisms of Resistance to Endocrine Therapies.

Prostate cancer (PCa) is a major global health concern. It ranks as the fifth leading cause of cancer-related mortality worldwide. While localized PCa is often indolent, with a nearly 100% five-year survival rate, prognosis worsens significantly in metastatic disease, where survival drops to approximately 30%. Androgen deprivation therapy (ADT) is initially effective in suppressing tumor growth. However, resistance eventually develops, resulting in castration-resistant prostate cancer (CRPC). The androgen receptor (AR) plays a central role in both PCa progression and treatment resistance. It promotes tumor growth by mediating the effects of testosterone and 5α-dihydrotestosterone (DHT). Several mechanisms contribute to resistance. These include AR gene mutations that reduce ligand specificity or convert antagonists into agonists. AR overexpression can maintain activity even at low androgen levels. Splice variants such as AR-V7 can activate AR signaling despite androgen depletion. AR transcriptional activity is also modulated by coregulators. Coactivators (such as the SRC family) and corepressors (such as NCOR1/2) contribute to the persistence of AR signaling. Beyond AR-dependent mechanisms, CRPC may develop through AR-independent pathways. These include glucocorticoid receptor (GR) bypass signaling and lineage plasticity leading to neuroendocrine prostate cancer (NEPC). In addition, intratumoral steroidogenesis sustains AR activation despite systemic suppression of androgens. Together, these resistance mechanisms underscore the biological complexity of CRPC. They also highlight the urgent need for innovative therapeutic approaches. This manuscript reviews emerging molecular targets and resistance pathways to inform the development of next-generation treatments.