Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability.
Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability.
复制标题
DOI：
10.1158/2159-8290.cd-21-0218
复制
发表时间：
2023-02-06
期刊：
影响因子：
28.2
通讯作者：
Majeti, Ravindra
中科院分区：
文献类型：
--
作者：
Thomas, Daniel;Wu, Manhong;Nakauchi, Yusuke;Zheng, Ming;Thompson-Peach, Chloe A. L.;Lim, Kelly;Landberg, Niklas;Koehnke, Thomas;Robinson, Nirmal;Kaur, Satinder;Kutyna, Monika;Stafford, Melissa;Hiwase, Devendra;Reinisch, Andreas;Peltz, Gary;Majeti, Ravindra
使用合成致死率和质谱法来鉴定具有IDH 1而非IDH 2突变的癌症中的新代谢脆弱性，这些突变在ivosidenib耐药性背景下是可靶向的。异柠檬酸脱氢酶1和2（IDH）在多种癌症中突变，并驱动（R）-2-羟基戊二酸（2 HG）的产生。我们确定了一种脂质合成酶[乙酰辅酶A羧化酶1（ACC 1）]作为突变IDH 1（mIDH 1）的合成致死靶点，但不是mIDH 2，癌症。在这里，我们分析了原发性急性髓性白血病（AML）原始细胞的代谢组，并确定了脂肪酸中mIDH 1特异性的减少。mIDH 1还诱导向β-氧化的转变，表明代谢向依赖脂肪酸的方向重新编程。与mIDH 2相比，mIDH 1 AML显示NADPH耗竭，还原性羧化缺陷，mIDH 1特异性抑制剂ivosidenib无法挽救。在异种移植模型中，无脂质饮食显著减缓了mIDH 1 AML的生长，但没有减缓健康的CD 34+造血干/祖细胞或mIDH 2 AML的生长。ACC 1的遗传和药理学靶向导致mIDH 1癌症的生长抑制不可逆的ivosidenib。重要的是，ACC 1的药理学靶向提高了mIDH 1 AML对维奈托克的敏感性。IDH 1和IDH 2中的致癌突变产生2-羟基戊二酸，并且通常认为在发病机制和靶向方面是等同的。使用全面的代谢组学分析，我们证明了突变IDH 1和IDH 2在具有靶向代谢干预的患者样本中脂肪酸代谢的意外代谢差异。 参见罗宾逊和莱文的相关评论，第266页。 这篇文章在本期专题中突出显示，第247页
Synthetic lethality and mass spectrometry were used to identify novel metabolic vulnerabilities in cancers with IDH1, but not IDH2, mutations that are targetable in the setting of ivosidenib resistance. Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified an mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax. Oncogenic mutations in both IDH1 and IDH2 produce 2-hydroxyglutarate and are generally considered equivalent in terms of pathogenesis and targeting. Using comprehensive metabolomic analysis, we demonstrate unexpected metabolic differences in fatty acid metabolism between mutant IDH1 and IDH2 in patient samples with targetable metabolic interventions. See related commentary by Robinson and Levine, p. 266. This article is highlighted in the In This Issue feature, p. 247
影响因子：
3.3
作者：
Wu, M.;Sahbaie, P.;Zheng, M.;Lobato, R.;Boison, D.;Clark, J. D.;Peltz, G.
通讯作者：
Peltz, G.