A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma.
A druggable addiction to de novo pyrimidine biosynthesis in diffuse midline glioma.
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DOI：
10.1016/j.ccell.2022.07.012
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发表时间：
2022-09-12
期刊：
影响因子：
50.3
通讯作者：
Haas-Kogan, Daphne A.
中科院分区：
文献类型：
--
作者：
Pal, Sharmistha;Kaplan, Jakub P.;Nguyen, Huy;Stopka, Sylwia A.;Savani, Milan R.;Regan, Michael S.;Nguyen, Quang-De;Jones, Kristen L.;Moreau, Lisa A.;Peng, Jingyu;Dipiazza, Marina G.;Perciaccante, Andrew J.;Zhu, Xiaoting;Hunsel, Bradley R.;Liu, Kevin X.;Alexandrescu, Sanda;Drissi, Rachid;Filbin, Mariella G.;McBrayer, Samuel K.;Agar, Nathalie Y. R.;Chowdhury, Dipanjan;Haas-Kogan, Daphne A.
弥漫性中线胶质瘤（DMG）是一种一致致命的儿童癌症，由肿瘤组蛋白驱动，不容易使自己适合药物开发。为了确定DMG的可药物靶点，我们进行了全基因组CRISPR筛选，揭示了DMG对嘧啶生物合成从头途径的选择性依赖。这种代谢脆弱性反映了尿嘧啶/尿嘧啶降解率的升高，这耗尽了DMG细胞中嘧啶生物合成替代补救途径的底物。DHODH（新生途径中的限速酶）的临床阶段抑制剂减少UMP池，产生DNA损伤，并通过抑制复制叉诱导细胞凋亡-一种“靶上”效应，如尿苷拯救所示。MALDI质谱成像显示，该DHODH抑制剂（BAY2402234）在脑内以治疗相关浓度积累，抑制体内新生嘧啶生物合成，并延长颅内DMG异种移植小鼠的生存期，突出BAY2402234是一种有前景的治疗DMG的方法。弥漫性中线胶质瘤（dmg）是致命的。Pal等人报道了DMG代谢依赖于从头合成嘧啶。这种依赖性的机制是嘧啶降解的上调。BAY2402234通过拮抗DHODH抑制新生嘧啶合成，延长DMG异种移植小鼠的生存期。
Diffuse midline glioma (DMG) is a uniformly fatal pediatric cancer driven by oncohistones that do not readily lend themselves to drug development. To identify druggable targets for DMG, we conducted a genome-wide CRISPR screen that reveals a DMG selective dependency on the de novo pathway for pyrimidine biosynthesis. This metabolic vulnerability reflects an elevated rate of uridine/uracil degradation that depletes DMG cells of substrates for the alternate salvage pathway for pyrimidine biosynthesis. A clinical stage inhibitor of DHODH (rate limiting enzyme in the de novo pathway) diminishes UMP pools, generates DNA damage, and induces apoptosis through suppression of replication forks--an “on target” effect, as shown by uridine rescue. MALDI mass spectroscopy imaging demonstrates that this DHODH inhibitor (BAY2402234) accumulates in brain at therapeutically relevant concentrations, suppresses de novo pyrimidine biosynthesis in vivo, and prolongs survival of mice bearing intracranial DMG xenografts, highlighting BAY2402234 as a promising therapy against DMGs. Diffuse midline gliomas (DMGs) are uniformly fatal. Pal et al. report a DMG metabolic dependency on de novo pyrimidine synthesis. The mechanism underlying this dependency is upregulation of pyrimidine degradation. BAY2402234 inhibits de novo pyrimidine synthesis by antagonizing DHODH and prolongs survival of DMG xenograft-bearing mice.
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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：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
14.8
作者：
Faubert, Brandon;Tasdogan, Alpaslan;Morrison, Sean J.;Mathews, Thomas P.;DeBerardinis, Ralph J.
通讯作者：
DeBerardinis, Ralph J.
影响因子：
28.2
作者：
Mathur D;Stratikopoulos E;Ozturk S;Steinbach N;Pegno S;Schoenfeld S;Yong R;Murty VV;Asara JM;Cantley LC;Parsons R
通讯作者：
Parsons R
DOI：
10.1126/science.aao4750
发表时间：
2018-04-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Filbin MG;Tirosh I;Hovestadt V;Shaw ML;Escalante LE;Mathewson ND;Neftel C;Frank N;Pelton K;Hebert CM;Haberler C;Yizhak K;Gojo J;Egervari K;Mount C;van Galen P;Bonal DM;Nguyen QD;Beck A;Sinai C;Czech T;Dorfer C;Goumnerova L;Lavarino C;Carcaboso AM;Mora J;Mylvaganam R;Luo CC;Peyrl A;Popović M;Azizi A;Batchelor TT;Frosch MP;Martinez-Lage M;Kieran MW;Bandopadhayay P;Beroukhim R;Fritsch G;Getz G;Rozenblatt-Rosen O;Wucherpfennig KW;Louis DN;Monje M;Slavc I;Ligon KL;Golub TR;Regev A;Bernstein BE;Suvà ML
通讯作者：
Suvà ML