BIRC6Targeting as Potential Therapy for Advanced, Enzalutamide-Resistant Prostate Cancer.
Purpose:Enzalutamide resistance has emerged as a major problem in the management of castration-resistant prostate cancer (CRPC). Research on therapy resistance of CRPCs has primarily focused on the androgen receptor pathway. In contrast, there is limited information on antiapoptotic mechanisms that may facilitate the treatment resistance. The inhibitor of apoptosis proteins (IAP) family is well recognized for its role in promoting treatment resistance of cancers by inhibiting drug-induced apoptosis. Here, we examined whether BIRC6, an IAP family member, has a role in enzalutamide resistance of CRPCs and could provide a therapeutic target for enzalutamide-resistant CRPC.Experimental Design:Use of enzalutamide-resistant CRPC models: (i) the transplantable, first high-fidelity LTL-313BR patient-derived enzalutamide-resistant CRPC tissue xenograft line showing primary enzalutamide resistance, (ii) MR42D and MR49F CRPC cells/xenografts showing acquired enzalutamide resistance. Specific BIRC6 downregulation in these models was produced using aBIRC6-targeting antisense oligonucleotide (ASO-6w2). Gene expression was determined by qRT-PCR and gene expression profiling. Molecular pathways associated with growth inhibition were assessed via gene enrichment analysis.Results:Of eight IAPs examined, BIRC6 was the only one showing elevated expression in both enzalutamide-resistant CRPC models. Treatment with ASO-6w2 markedly suppressed growth of LTL-313BR xenografts and increased tumor apoptosis without inducing major host toxicity. Pathway enrichment analysis indicated that GPCR and matrisome signaling were the most significantly altered pathways. Furthermore, ASO-6w2 inhibited expression of prosurvival genes that were upregulated in the LTL-313BR line.Conclusions:BIRC6targeting inhibited the growth of enzalutamide-resistant CRPC models and may represent a new option for clinical treatment of advanced, enzalutamide-resistant prostate cancer.Clin Cancer Res; 23(6); 1542-51. ©2016 AACR.
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Iris Sze Ue
IS
Luk
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Raunak
R
Shrestha
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Hui
H
Xue
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Yuwei
Y
Wang
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Fang
F
Zhang
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Dong
D
Lin
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Anne
A
Haegert
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Rebecca
R
Wu
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Xin
X
Dong
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Colin C
CC
Collins
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Amina
A
Zoubeidi
Vancouver Prostate Centre, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Martin E
ME
Gleave
Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.
Peter W
PW
Gout
Vancouver Prostate Centre, Vancouver, British Columbia, Canada. ywang@bccrc.ca.|Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, British Columbia, Canada.|Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Yuzhuo
Y
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D051379:Mice; D009570:Nitriles; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; C401541:BIRC6 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; D009570:Nitriles; D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide