癌症中的NAD代谢依赖是由基因放大和增强器重塑形成的
Sudhir Chowdhry1, Ciro Zanca1, Utkrisht Rajkumar2
1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
Nature
|April 26, 2019
概括
癌细胞的生存取决于组织类型,这决定了对特定的尼古丁胺氨基二核酸 (NAD) 合成途径的依赖. 这一发现解释了治疗失败,并指导了针对癌症代谢的新精确瘤学策略.
科学领域:
- 癌症学
- 癌症新陈代谢
- 分子生物学
背景情况:
- 精确瘤学旨在将向药物与瘤基因型相匹配.
- 针对癌症的新陈代谢失调仍然是一个重大挑战.
- 尼古丁胺氨基二核酸 (NAD) 的代谢在癌症中经常发生改变.
研究的目的:
- 研究组织环境在确定癌细胞依赖NAD代谢途径中的作用.
- 在不同类型的癌症中确定管理NAD路径的可操作规则.
- 解释针对NAD合成酶的有效性和局限性.
主要方法:
- 分析了超过7000个瘤和2600个正常组织样本,
- 对NAD代谢的数学建模.
- 在体外和体内实验验证.
主要成果:
- 组织环境决定了癌细胞依赖于新的或挽救的NAD合成途径.
- 来自高NAPRT表达的组织的癌症取决于NAPRT放大.
- 来自低NAPRT表达组织的瘤依赖于救援途径,并确定了增强剂.
- 在药理上,NAPRT放大产生了可操作的漏洞.
- 耐NAMPT抑制剂与依赖NMRK1的NAD合成有关.
结论:
- 组织环境是癌症中NAD代谢途径依赖的关键决定因素.
- 这项研究解释了某些NAMPT抑制剂的失效.
- 这些发现为开发针对NAD代谢的新型特定癌症疗法提供了框架.
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