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Abstract Androgen deprivation therapy has achieved significant success in treating prostate cancer through strategies centered on the androgen receptor. However, the emergence of castration‐resistant prostate cancer highlights this therapy limitation, underscoring the need to elucidate the mechanisms of treatment resistance. This review aimed to focus on multifaceted resistance mechanisms, including androgen receptor overexpression, splice variants, missense mutations, the involvement of the glucocorticoid receptor, and alterations in coregulators and transcription factors, revealing their roles in castration‐resistant prostate cancer progression. These mechanisms promote cell survival and proliferation, depending on the androgen receptor signaling pathway, leading to resistance to conventional therapies. Amplification and mutations in the androgen receptor gene facilitate selective adaptation in treatment‐resistant cells, consequently diminishing therapeutic efficacy. Furthermore, the activation of glucocorticoid receptors and aberrant regulation of specific coregulators and transcription factors contribute to the activation of androgen receptor‐independent signaling pathways, promoting cell survival and proliferation. These findings hold promise for identifying new targets for treating castration‐resistant prostate cancer and developing personalized treatment strategies. The development of future therapies will hinge on precisely targeting the androgen receptor signaling pathway, necessitating a deeper understanding of the molecular targets unique to castration‐resistant prostate cancer.
Obinata et al. (Mon,) studied this question.