title: Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting.
abstract: While there are myriad mechanisms of primary and acquired resistance to conventional and next-generation hormonal therapies in prostate cancer, the potential role of androgen receptor splice variants (AR-Vs) has recently gained momentum. AR-Vs are abnormally truncated isoforms of the androgen receptor (AR) protein that lack the COOH-terminal domain but retain the NH2-terminal domain and DNA-binding domain and are thus constitutively active even in the absence of ligands. Although multiple preclinical studies have previously implicated AR-Vs in the development of castration resistance as well as resistance to abiraterone and enzalutamide, recent technological advances have made it possible to reliably detect and quantify AR-Vs from human clinical tumor specimens including blood samples. Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells. Efforts are now underway to clinically validate AR-V7 as a relevant treatment-selection biomarker in the context of other key genomic aberrations in men with metastatic castration-resistant prostate cancer. Additional efforts are underway to therapeutically target both AR and AR-Vs either directly or indirectly. Whether AR-Vs represent drivers of castration-resistant prostate cancer, or whether they are simply passenger events associated with aggressive disease or clonal heterogeneity, will ultimately be answered only through these types of clinical trials.
authors.affiliation: Departments of Oncology and Urology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Antonarakis
authors.affiliation: Departments of Medicine, Surgery, and Pharmacology and Cancer Biology, Divisions of Medical Oncology and Urology, Duke Cancer Institute, Durham, NC, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Armstrong
authors.affiliation: Masonic Cancer Center and Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Dehm
authors.affiliation: Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Luo
mesh_terms: D017398:Alternative Splicing; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use; D000728:Androgens / Q000378:metabolism; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011944:Receptors, Androgen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012106:Research; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic; D016896:Treatment Outcome
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen