Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition.
Activation of the NRF2 antioxidant program sensitizes tumors to G6PD inhibition.
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DOI：
10.1126/sciadv.abk1023
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发表时间：
2021-11-19
期刊：
影响因子：
13.6
通讯作者：
Papagiannakopoulos T
中科院分区：
文献类型：
--
作者：
Ding H;Chen Z;Wu K;Huang SM;Wu WL;LeBoeuf SE;Pillai RG;Rabinowitz JD;Papagiannakopoulos T
在nrf2激活的肿瘤中，G6pd抑制会耗尽TCA中间体并抑制肿瘤生长。KEAP1/NRF2通路促进代谢重布线以支持氧化还原稳态。NRF2的激活发生在许多癌症中，通常是由于KEAP1突变，并且与更具侵袭性的疾病和治疗耐药性相关。为了确定NRF2激活的癌症中的代谢依赖性，我们进行了以代谢为重点的CRISPR筛选。葡萄糖-6-磷酸脱氢酶（G6PD）最近被证明在ras驱动的肿瘤中是不可缺少的，是最重要的依赖物。G6PD催化氧化戊糖磷酸途径的既定步骤，产生NADPH和核苷酸前体，但抗氧化剂和核苷都没有得救。相反，G6PD缺失引发了三羧酸（TCA）中间体耗散，这是由于替代nadph产生酶苹果酸酶和异柠檬酸脱氢酶的上调。在体内，G6PD损伤显著抑制KEAP1突变体的肿瘤生长，这种抑制作用通过谷氨酰胺酶抑制TCA的消耗进一步增强。因此，G6PD抑制诱导的TCA缺失是nrf2激活的癌症的治疗脆弱性。
In Nrf2-activated tumors, G6pd inhibition depletes TCA intermediates and suppresses tumor growth. The KEAP1/NRF2 pathway promotes metabolic rewiring to support redox homeostasis. Activation of NRF2 occurs in many cancers, often due to KEAP1 mutations, and is associated with more aggressive disease and treatment resistance. To identify metabolic dependencies in cancers with NRF2 activation, we performed a metabolism-focused CRISPR screen. Glucose-6-phosphate dehydrogenase (G6PD), which was recently shown to be dispensable in Ras-driven tumors, was a top dependency. G6PD catalyzes the committed step of the oxidative pentose phosphate pathway that produces NADPH and nucleotide precursors, but neither antioxidants nor nucleosides rescued. Instead, G6PD loss triggered tricarboxylic acid (TCA) intermediate depletion because of up-regulation of the alternative NADPH-producing enzymes malic enzyme and isocitrate dehydrogenase. In vivo, G6PD impairment markedly suppressed KEAP1 mutant tumor growth, and this suppression was further augmented by TCA depletion by glutaminase inhibition. Thus, G6PD inhibition–induced TCA depletion is a therapeutic vulnerability of NRF2-activated cancer.
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影响因子：
11.2
作者：
Galan-Cobo, Ana;Sitthideatphaiboon, Piyada;Heymach, John, V
通讯作者：
Heymach, John, V
影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
同时发生的基因组改变对KRAS突变非小细胞肺癌患者结局的影响。
DOI：
10.1158/1078-0432.ccr-17-1841
发表时间：
2018-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arbour KC;Jordan E;Kim HR;Dienstag J;Yu HA;Sanchez-Vega F;Lito P;Berger M;Solit DB;Hellmann M;Kris MG;Rudin CM;Ni A;Arcila M;Ladanyi M;Riely GJ
通讯作者：
Riely GJ
影响因子：
--
作者：
Fabrizio FP;Costantini M;Copetti M;la Torre A;Sparaneo A;Fontana A;Poeta L;Gallucci M;Sentinelli S;Graziano P;Parente P;Pompeo V;De Salvo L;Simone G;Papalia R;Picardo F;Balsamo T;Flammia GP;Trombetta D;Pantalone A;Kok K;Paranita F;Muscarella LA;Fazio VM
通讯作者：
Fazio VM
影响因子：
16.6
作者：
Best, Sarah A.;Ding, Sheryl;Sutherland, Kate D.
通讯作者：
Sutherland, Kate D.