title: Androgen pathway resistance in prostate cancer and therapeutic implications.
abstract: BACKGROUND
  Metastatic prostate cancer is an incurable disease that is treated with a variety of hormonal therapies targeting various nodes of the androgen receptor (AR) pathway. Invariably patients develop resistance and become castration resistant. Common treatments for castration-resistant disease include novel hormonal therapies, such as abiraterone and enzalutamide, chemotherapy, immunotherapy and radiopharmaceuticals. As this disease generally remains incurable, understanding the molecular underpinnings of resistance pathways is critical in designing therapeutic strategies to delay or overcome such resistance.
  
  
  METHODS
  This review will explore the resistance mechanisms relevant to hormonal agents, such as AR-V7 expression and others, as well as discussing new approaches being developed to treat patients with castration-resistant prostate cancer that take advantage of these new insights. A literature search was performed to identify all published clinical trials related to androgen therapy mechanisms of drug resistance in metastatic castration-resistant prostate cancer.
  
  
  CONCLUSIONS
  Androgen therapy resistance mechanisms are varied, and include modification of all nodes in the androgen signaling pathway. The optimal treatment for men with relapsed metastatic castration-resistant prostate cancer is uncertain at this time. The authors recommend using available clinical data to guide treatment decision making until more specific biomarkers are clinically available.
authors.affiliation: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center , 1650 Orleans St. CRB1 186, Baltimore, MD USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Maughan
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Antonarakis
mesh_terms: D000728:Androgens / Q000378:metabolism* / Q000627:therapeutic use; D000736:Androstenes / Q000627:therapeutic use; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019154:Protein Splicing; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000728:Androgens; D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone
keywords: AR-V7; androgen receptor; hormone resistance; metastatic castration-resistant prostate cancer; treatment sequence