Abstract
Simple SummaryProstate 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.
Highlights
A mechanism of therapy resistance by androgen receptor (AR) antagonists may be explained by the findings that Enz and Bic induce autophagy leading to a pro-survival response in prostate cancer (PCa) cells [93,97]
Since the transformation of PCa to neuroendocrine PCa (NEPC) is thought to develop a resistant mechanism to AR-directed therapies, N-Myc and ONECUT2 are suggested as a promising target in castration resistant PCa (CRPC) therapy
Another pathway that involves STAT3 is an aberrant TGF-β pathway that plays a major function in the occurrence of DRPC and induction of epithelial-mesenchymal transition (EMT) because members of TGF-β family induce the expression of Snail [146]
Summary
Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of cancer deaths in males in Western countries [1]. Androgen-deprivation therapy including cancer -associated fibroblasts and immune cells). Associated tumor and other PCa therapeutic drugs,toincluding chemotherapy radiation, might select forwith drugthe resistant evolution, duringtotumorigenesis. AR antagonists can induce cellular senescence in PCa cells in vitro. AR antagonists can induce cellular senescence in PCa cells in vitro as well as ex vivo in patients. This indicates that AR antagonists not pletely inhibit the in ARpatients rather promote the induction of an AR-dependent cellulardosenescompletely inhibit the rather promote the induction of an AR-dependent cellular cence pathway [11,12,13]. PCa through senescent cells might be one mechanism of tumor evolution towards antagonist resistance.
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