肿瘤精准医学有赖于将肿瘤基因型与分子靶向药物进行关联；不过，如何靶向多变的肿瘤细胞代谢谱已被证实非常困难。烟酰胺腺嘌呤二核苷酸（NAD）又称辅酶Ⅰ，是细胞氧化代谢的电子载体，其烟酰胺环可以接受一个氢离子和两个电子。最近研究发现NAD与肿瘤发生密切相关，可以促进衰老细胞分泌促炎因子，刺激肿瘤细胞生长。哺乳动物细胞通过三条途径合成NAD：一是以色氨酸为原料的从头合成途径，二是以烟酸为原料的合成途径，三是以烟酰胺或烟酰胺核苷为原料的补救合成途径。不过，决定NAD合成途径选择方式的分子机制尚不明确。
2019年4月24日，全球自然科学三大旗舰期刊之一、英国《自然》正刊在线发表美国圣迭戈加利福尼亚大学、杜克大学、上海交通大学医学院附属瑞金医院国家转化医学研究中心的研究报告，发现肿瘤组织环境是肿瘤细胞NAD代谢途径的主要决定因素，以及针对NAD代谢基因型选择靶向药物进行肿瘤精准治疗的潜在途径。
该研究对19种肿瘤组织类型超过7000个肿瘤标本和2600个匹配正常样本进行分析，结合数学模型和广泛的体外和体内分析，确定了一套简单易行的肿瘤靶向治疗新“规则”。如果NAD从头合成限速酶——烟酸磷酸核糖转移酶（NAPRT）高表达于正常组织类型，那么来源于该组织的肿瘤也将高表达NAPRT，并且完全且不可逆地依赖于NAPRT而生存。相反，来源于低表达NAPRT正常组织的肿瘤将完全依赖于NAD补救合成途径而生存。随后，该研究发现了增强该依赖性的基因转录启动序列。NAPRT高表达可以产生肿瘤细胞生存的依赖性，并且可以通过药物进行靶向治疗。
因此，该研究结果表明，可以根据不同肿瘤组织的NAD生物合成途径，利用NAMPT抑制剂进行更为有效的靶向治疗。
Nature. 2019 Apr 24. [Epub ahead of print]
NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling.
Chowdhry S, Zanca C, Rajkumar U, Koga T, Diao Y, Raviram R, Liu F, Turner K, Yang H, Brunk E, Bi J, Furnari F, Bafna V, Ren B, Mischel PS.
University of California at San Diego, La Jolla, CA, USA; Duke University School of Medicine, Durham, NC, USA; National Research Center for Translational Medicine, Ruijin Hospital, Shanghai, China; UC San Diego School of Medicine, La Jolla, CA, USA.
Precision oncology hinges on linking tumour genotype with molecularly targeted drugs; however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge. 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.
PMID: 31019297
DOI: 10.1038/s41586-019-1150-2
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