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

机译：NAD癌症的代谢依赖性通过基因扩增和增强剂重塑而成

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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：用分子靶向药物将肿瘤基因型连接的精密肿瘤铰链（1）;然而，靶向癌症的经常失调的代谢景观已被证明是一个重大挑战（2）。在这里，我们表明组织背景是依赖于尼古林酰胺腺嘌呤二核苷酸（NAD）代谢途径在癌症中的主要决定因素。通过分析超过7,000种肿瘤和2,600种匹配的19种组织类型的匹配正常样本，与数学建模和体外大规模和体内分析相结合，我们确定了一个简单而可行的“规则”。如果DE Novo NAD合成的速率限制酶，NAPRT在正常的组织类型中高度表达，因此从该组织产生的癌症将具有高频率的NAPRT扩增，并且完全且不可逆地依赖于NAPRT以进行存活。相比之下，从不表达NAPRT的正常组织产生的肿瘤完全依赖于NAD挽救途径以存活。我们确定了以前未知的增强器，使这种依赖性提出。显示NAPRT的扩增显示在药物上可操作的肿瘤细胞依赖性的存活率。依赖于NAD合成途径的另一种速率限制酶，NAMPT作为增强子重塑的结果受NMRK1依赖性合成的抗性受阻。这些结果鉴定了组织背景在确定NAD生物合成途径的选择时的核心作用，解释了命名抑制剂的失败，并为更有效的治疗铺平道路。

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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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