Generation 2.5 Antisense Oligonucleotides Targeting the Androgen Receptor and Its Splice Variants Suppress Enzalutamide-Resistant Prostate Cancer Cell Growth

DOI PDF PubMed 被引用文献5件
  • Yoshiaki Yamamoto
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Yohann Loriot
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Eliana Beraldi
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Fan Zhang
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Alexander W. Wyatt
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Nader Al Nakouzi
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Fan Mo
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Tianyuan Zhou
    3Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California.
  • Youngsoo Kim
    3Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California.
  • Brett P. Monia
    3Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California.
  • A. Robert MacLeod
    3Department of Antisense Drug Discovery, Isis Pharmaceuticals Inc., Carlsbad, California.
  • Ladan Fazli
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Yuzhuo Wang
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Colin C. Collins
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Amina Zoubeidi
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
  • Martin Gleave
    1The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

書誌事項

公開日
2015-03-31
DOI
  • 10.1158/1078-0432.ccr-14-1108
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title> <jats:p>Purpose: Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full-length (ARFL) or variants (AR-Vs) in disease progression.</jats:p> <jats:p>Experimental Design: To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon-1, intron-1, and exon-8 in AR pre-mRNA to knockdown ARFL alone or with AR-Vs, and examined their effects in three CRPC cell lines and patient-derived xenografts.</jats:p> <jats:p>Results: ENZ-R-LNCaP cells express high levels of both ARFL and AR-V7 compared with CRPC-LNCaP; in particular, ARFL levels were approximately 12-fold higher than AR-V7. Both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP cells even in the absence of exogenous androgens. In ENZ-R-LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression, and delayed tumor growth in vivo. In 22Rv1 cells that are inherently ENZ-resistant, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity, and AR-regulated gene expression than knockdown of ARFL alone. Exon-1 AR-ASO also inhibited tumor growth of LTL-313BR patient-derived CRPC xenografts.</jats:p> <jats:p>Conclusions: These data identify the AR as an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC. Clin Cancer Res; 21(7); 1675–87. ©2015 AACR.</jats:p>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 21 (7), 1675-1687, 2015-03-31

    American Association for Cancer Research (AACR)

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