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NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling

机译：NAD对癌症的代谢依赖性取决于基因扩增和增强子重塑

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摘要

Precision oncology hinges on linking tumour genotype with molecularly targeted drugs(1); however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge(2). Here we show that tissue context is the major determinant of dependence on the nicotinamide adenine dinucleotide (NAD) metabolic pathway in cancer. By analysing more than 7,000 tumours and 2,600 matched normal samples of 19 tissue types, coupled with mathematical modelling and extensive in vitro and in vivo analyses, we identify a simple and actionable set of 'rules'. If the rate-limiting enzyme of de novo NAD synthesis, NAPRT, is highly expressed in a normal tissue type, cancers that arise from that tissue will have a high frequency of NAPRT amplification and be completely and irreversibly dependent on NAPRT for survival. By contrast, tumours that arise from normal tissues that do not express NAPRT highly are entirely dependent on the NAD salvage pathway for survival. We identify the previously unknown enhancer that underlies this dependence. Amplification of NAPRT is shown to generate a pharmacologically actionable tumour cell dependence for survival. Dependence on another rate-limiting enzyme of the NAD synthesis pathway, NAMPT, as a result of enhancer remodelling is subject to resistance by NMRK1-dependent synthesis of NAD. These results identify a central role for tissue context in determining the choice of NAD biosynthetic pathway, explain the failure of NAMPT inhibitors, and pave the way for more effective treatments.
机译：精准肿瘤学取决于将肿瘤基因型与分子靶向药物联系起来（1）;然而，针对经常代谢失调的癌症新陈代谢被证明是一项重大挑战（2）。在这里，我们显示组织背景是癌症中对烟酰胺腺嘌呤二核苷酸（NAD）代谢途径的依赖的主要决定因素。通过分析19个组织类型的7,000多个肿瘤和2,600个匹配的正常样本，再加上数学模型以及广泛的体内和体外分析，我们确定了一套简单且可行的“规则”。如果从头NAD合成的限速酶NAPRT在正常组织类型中高表达，则由该组织引起的癌症将具有高频率的NAPRT扩增，并且完全不可逆转地依赖于NAPRT来维持生存。相比之下，源自不高度表达NAPRT的正常组织的肿瘤完全取决于NAD挽救途径的生存。我们确定了这种依赖性基础的先前未知的增强子。 NAPRT的扩增显示可产生药理作用的肿瘤细胞生存依赖。作为增强子重塑的结果，对NAD合成途径的另一种限速酶NAMPT的依赖性受到NAD NMRK1依赖性合成的抵抗。这些结果确定了组织环境在确定NAD生物合成途径选择中的核心作用，解释了NAMPT抑制剂的失败，并为更有效的治疗铺平了道路。

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  • 来源
    《Nature》 |2019年第7757期|570-575|共6页
  • 作者

    Chowdhry Sudhir; Zanca Ciro; Rajkumar Utkrisht; Koga Tomoyuki; Diao Yarui; Raviram Ramya; Liu Feng; Turner Kristen; Yang Huijun; Brunk Elizabeth; Bi Junfeng; Furnari Frank; Bafna Vineet; Ren Bing; Mischel Paul S.;

  • 作者单位

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Duke Univ, Sch Med, Dept Cell Biol, Regenerat Next Initiat, Durham, NC USA|Duke Univ, Sch Med, Dept Orthopaed Surg, Regenerat Next Initiat, Durham, NC USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Ruijin Hosp, Natl Res Ctr Translat Med, Shanghai, Peoples R China;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Cellular & Mol Med, Ctr Epigen, Sch Med, La Jolla, CA USA|Univ Calif San Diego, Moores Canc Ctr, Sch Med, La Jolla, CA USA;

    Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA|Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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