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The androgen/androgen receptor (AR) axis represents a key driver of treatment resistance in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) and targeted agents, and a deeper comprehension of resistance mechanisms is fundamental to adopt effective therapeutic strategies. We review the mechanisms of primary or secondary resistance to hormone therapy (HT) in PCa, especially focusing on available data and emerging evidence. First- and second-generation HT resistance has been associated with several AR-dependent and AR-independent mechanisms, ranging from the amplification of the AR gene locus to somatic AR mutations and the intratumoral synthesis of androgens from adrenal steroids and cholesterol. As reported in the current review, the development of novel and effective treatments is needed to personalize anticancer therapies in this setting and to finally improve clinical outcomes in patients with HT-resistant disease.

Adapting to hormone-therapy resistance for adopting the right therapeutic strategy in advanced prostate cancer