NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling
NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling
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DOI：
10.1038/s41586-019-1150-2
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发表时间：
2019-05-23
期刊：
影响因子：
64.8
通讯作者：
Mischel, Paul S.
中科院分区：
文献类型：
--
作者：
Chowdhry, Sudhir;Zanca, Ciro;Mischel, Paul S.
精确的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，靶向癌症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，组织环境是依赖于烟酰胺腺嘌呤二核苷酸（NAD）代谢途径的癌症的主要决定因素。通过分析19种组织类型的7，000多个肿瘤和2，600个匹配的正常样本，再加上数学建模和广泛的体外和体内分析，我们确定了一套简单且可操作的“规则”。如果NAD从头合成的限速酶NAPRT在正常组织类型中高度表达，则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生存。相比之下，来自不高度表达NAPRT的正常组织的肿瘤完全依赖于NAD挽救途径存活。我们确定了以前未知的增强子，这种依赖的基础。NAPRT的扩增显示出产生可消除的肿瘤细胞存活依赖性。依赖于另一种限速酶的NAD合成途径，NAMPT，作为增强子重塑的结果是受到阻力NMRK 1依赖性合成的NAD。这些结果确定了组织背景在决定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。
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.