Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer.

Androgen receptor (AR) is a main driver of prostate cancer (PCa) growth and progression as well as the key drug target. Appropriate PCa treatments differ depending on the stage of cancer at diagnosis. Although androgen deprivation therapy (ADT) of PCa is initially effective, eventually tumors develop resistance to the drug within 2-3 years of treatment onset leading to castration resistant PCa (CRPC). Castration resistance is usually mediated by reactivation of AR signaling. Eventually, PCa develops additional resistance towards treatment with AR antagonists that occur regularly, also mostly due to bypass mechanisms that activate AR signaling. This tumor evolution with selection upon therapy is presumably based on a high degree of tumor heterogenicity and plasticity that allows PCa cells to proliferate and develop adaptive signaling to the treatment and evolve pathways in therapy resistance, including resistance to chemotherapy. The therapy-resistant PCa phenotype is associated with more aggressiveness and increased metastatic ability. By far, drug resistance remains a major cause of PCa treatment failure and lethality. In this review, various acquired and intrinsic mechanisms that are AR­dependent and contribute to PCa drug resistance will be discussed.