title: Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms.
abstract: Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspase-dependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Centenera
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Gillis
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Marrocco-Tallarigo
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Randall H
authors.initials: RH
authors.lastname: Grose
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia Dame Roma Mitchell Cancer Research Laboratories Adelaide Prostate Cancer Research Centre and Freemason's Foundation Centre for Men's Health, School of Medicine, University of Adelaide, Adelaide, Australia South Australian Health and Medical Research Institute PO Box 11060, Adelaide, South Australia 5001, Australia lisa.butler@adelaide.edu.au.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007124:Immunoenzyme Techniques; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008297:Male; D009570:Nitriles / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000813:Anilides; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009570:Nitriles; D012333:RNA, Messenger; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C112765:tanespimycin; C053541:bicalutamide
keywords: androgen receptor; combination; heat shock protein; prostate cancer