title: Targeting persistent androgen receptor signaling in castration-resistant prostate cancer.
abstract: Castration-resistant prostate cancer (CRPC), the invariably lethal phenotype of advanced prostate cancer, represents a clinical state defined by disease progression despite reduction of testosterone to castrate levels (i.e., ≤50 ng/dL). Although resistant to androgen-deprivation therapy (i.e., LHRH agonists/antagonists), CRPC continues to depend on the androgen receptor (AR)-signaling pathway. Supporting the importance of AR-signaling in a castration-resistant state, the next-generation AR-signaling inhibitors enzalutamide and abiraterone have been shown to afford a survival benefit in men with metastatic CRPC. However, primary and secondary resistance mechanisms to these agents inevitably drive continued disease progression-often as a result of re-activation of AR-signaling. With increased understanding of the mechanisms underlying how continued AR-signaling occurs in spite of drugs like abiraterone and enzalutamide, a new wave of therapies is emerging designed to more effectively target AR-signaling. This review will focus on the more clinically relevant mechanisms of CRPC drug resistance and our ongoing efforts to develop drugs to target these mechanisms.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA, 98104, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Graham
authors.affiliation: Division of Oncology, Department of Medicine, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. schweize@uw.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Schweizer
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000736:Androstenes / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D059002:Androgen Receptor Antagonists; D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone
keywords: Abiraterone; Androgen receptor; Androgen receptor splice variant; Androgen-deprivation therapy; Castration-resistant prostate cancer; Drug resistance; Enzalutamide; Hormonal therapy