ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.
ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways.
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DOI：
10.1038/s41467-017-00221-3
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发表时间：
2017-08-14
影响因子：
16.6
通讯作者：
Radu CG
中科院分区：
文献类型：
--
作者：
Le TM;Poddar S;Capri JR;Abt ER;Kim W;Wei L;Uong NT;Cheng CM;Braas D;Nikanjam M;Rix P;Merkurjev D;Zaretsky J;Kornblum HI;Ribas A;Herschman HR;Whitelegge J;Faull KF;Donahue TR;Czernin J;Radu CG
白血病细胞依赖于两种核苷酸生物合成途径，从头和补救，以产生用于DNA复制的dNTP。在这里，使用代谢组学，蛋白质组学和磷酸蛋白质组学的方法，我们表明，抑制复制应激感应激酶共济失调毛细血管扩张和Rad 3相关蛋白（ATR）减少输出的从头和补救途径，通过调节各自的限速酶，核糖核苷酸还原酶（RNR）和脱氧胞苷激酶（dCK）的活性，通过不同的分子机制。ATR抑制的急性淋巴细胞白血病（ALL）细胞中核苷酸生物合成的定量显示了大量剩余的从头和挽救活性，并且不能在体内消除疾病。然而，用RNR和dCK抑制剂靶向这些剩余的活性在体外触发了致命的复制应激，并在B-ALL小鼠中实现了长期无病生存，而没有可检测到的毒性。因此，替代核苷酸生物合成途径和ATR之间的功能相互作用为白血病和潜在的其他癌症提供了治疗机会。白血病细胞依赖于核苷酸合成途径来增殖。在这里，作者使用代谢组学和蛋白质组学来表明ATR的抑制降低了这些途径的活性，从而为白血病提供了一个有价值的治疗靶点。
Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers. Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
Zou L
DOI：
10.1084/jem.20121061
发表时间：
2012-11-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Austin WR;Armijo AL;Campbell DO;Singh AS;Hsieh T;Nathanson D;Herschman HR;Phelps ME;Witte ON;Czernin J;Radu CG
通讯作者：
Radu CG
影响因子：
20.3
作者：
Boulos, Nidal;Mulder, Heather L.;Williams, Richard T.
通讯作者：
Williams, Richard T.
影响因子：
5.8
作者：
Beyaert, Maxime;Starczewska, Eliza;Bontemps, Francoise
通讯作者：
Bontemps, Francoise