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Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer

机译:BET溴结构域蛋白在去势抵抗性前列腺癌中的治疗靶向

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摘要

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after andro-gen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with theN-terminal domain of AR and can be disrupted by JQ1. like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.
机译:发生转移性去势抵抗性前列腺癌(CRPC)的男人总是死于这种疾病。雄激素消融治疗后向CRPC的进展主要受雄激素受体(AR)信号失控的驱动。尽管最近批准的针对AR信号的疗法取得了成功,例如阿比特龙和包括MDV3100(也称为enzalutamide)在内的第二代抗雄激素药,但持久的反应仍然有限,大概是由于获得性耐药。最近,已经证明靶向BRD4氨基末端溴结构域的两种选择性小分子抑制剂JQ1和I-BET762在一系列恶性肿瘤中均表现出抗增殖作用。在这里,我们显示了具有AR信号传递能力的人类CRPC细胞系对溴结构域和末端(BET)抑制具有优先敏感性。 BRD4与AR的N末端域发生物理相互作用,并可能被JQ1破坏。就像直接的AR拮抗剂MDV3100一样,JQ1破坏了AR向目标基因位点的募集。与MDV3100相反,JQ1在AR的下游起作用,并且更有效地废除了BRD4定位于AR目标基因座和AR介导的基因转录,包括诱导TMPRSS2-ERG基因融合及其致癌活性。在体内,在CRPC异种移植小鼠模型中,BET溴结构域抑制比直接AR拮抗作用更有效。综上所述,这些研究为协同阻断晚期前列腺癌致癌驱动因子提供了一种新的表观遗传学方法。

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  • 来源
    《Nature》 |2014年第7504期|278-282|共5页
  • 作者单位

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA;

    Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

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