title: Targeting Androgen Receptor Activation Function-1 with EPI to Overcome Resistance Mechanisms in Castration-Resistant Prostate Cancer.
abstract: OBJECTIVE
  Persistent androgen receptor (AR) transcriptional activity is clinically evident in castration-resistant prostate cancer (CRPC). Therefore, AR remains as a viable therapeutic target for CRPC. All current hormonal therapies target the C-terminus ligand-binding domain (LBD) of AR. By using EPI to target AR activation function-1 (AF-1), in the N-terminal domain that is essential for AR transactivation, we evaluate the ability of EPI to overcome several clinically relevant AR-related mechanisms of resistance.
  
  
  METHODS
  To study the effect of EPI on AR transcriptional activity against overexpressed coactivators, such as SRC1-3 and p300, luciferase reporter assays were performed using LNCaP cells. AR-negative COS-1 cells were employed for reporter assays to examine whether the length of polyglutamine tract affects inhibition by EPI. The effect of EPI on constitutively active AR splice variants was studied in LNCaP95 cells, which express AR-V7 variant. To evaluate the effect of EPI on the proliferation of LNCaP95 cells, we performed in vitro BrdUrd incorporation assay and in vivo studies using xenografts in mice.
  
  
  RESULTS
  EPI effectively overcame several molecular alterations underlying aberrant AR activity, including overexpressed coactivators, AR gain-of-function mutations, and constitutively active AR-V7. EPI inhibited AR transcriptional activity regardless of the length of polyglutamine tract. Importantly, EPI significantly inhibited the in vitro and in vivo proliferation of LNCaP95 prostate cancer cells, which are androgen independent and enzalutamide resistant.
  
  
  CONCLUSIONS
  These findings support EPI as a promising therapeutic agent to treat CRPC, particularly against tumors driven by constitutively active AR splice variants that are resistant to LBD-targeting drugs. Clin Cancer Res; 22(17); 4466-77. ©2016 AACRSee related commentary by Sharp et al., p. 4280.
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Yu Chi
authors.initials: YC
authors.lastname: Yang
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Carmen Adriana
authors.initials: CA
authors.lastname: Banuelos
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Haile
authors.affiliation: School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland.
authors.forename: Iain J
authors.initials: IJ
authors.lastname: McEwan
authors.affiliation: Department of Medicine, University of Washington, Harborview Medical Center, Seattle, Washington.
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
authors.affiliation: Department of Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. msadar@bcgsc.ca.
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002728:Chlorohydrins / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D023041:Xenograft Model Antitumor Assays
chemical_list: D059002:Androgen Receptor Antagonists; D001559:Benzhydryl Compounds; D002728:Chlorohydrins; C000624374:EPI-506; D011944:Receptors, Androgen