Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

Simple Summary Prostate cancer can develop under hormone treatment and chemotherapy from a castration-sensitive towards a castration-resistant into a drug resistant-tumor. The main hormonal drug target is the androgen receptor (AR). Androgen deprivation therapy reduces body-own androgen production and AR antagonists inhibit androgen-mediated activation of AR. Here, molecular mechanisms are described that review knowledge about tumor cells escape therapy by developing bypass mechanisms of AR-signaling. This includes genomic and non-genomic signaling. Deciphering the involved molecules that mediate castration and drug resistance will provide the basis of potential novel drug targets that may be used in addition to AR inhibition as combinatory treatment. 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 AR-dependent and contribute to PCa drug resistance will be discussed.

Automated summary

Prostate cancer can develop resistance to hormone treatment and chemotherapy, mainly due to the androgen receptor (AR). There are genomic and non-genomic signaling bypass mechanisms that tumor cells may develop to escape therapy. As resistance progresses, tumors may evolve further adaptive pathways which lead to increased aggressiveness and metastatic ability.