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De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma
Cancer Cell ( IF 48.8 ) Pub Date : 2022-08-18 , DOI: 10.1016/j.ccell.2022.07.011
Diana D Shi 1 , Milan R Savani 2 , Michael M Levitt 3 , Adam C Wang 4 , Jennifer E Endress 5 , Cylaina E Bird 6 , Joseph Buehler 3 , Sylwia A Stopka 7 , Michael S Regan 8 , Yu-Fen Lin 9 , Vinesh T Puliyappadamba 3 , Wenhua Gao 4 , Januka Khanal 4 , Laura Evans 10 , Joyce H Lee 4 , Lei Guo 11 , Yi Xiao 3 , Min Xu 3 , Bofu Huang 4 , Rebecca B Jennings 12 , Dennis M Bonal 13 , Misty S Martin-Sandoval 3 , Tammie Dang 14 , Lauren C Gattie 15 , Amy B Cameron 13 , Sungwoo Lee 16 , John M Asara 17 , Harley I Kornblum 18 , Tak W Mak 19 , Ryan E Looper 20 , Quang-De Nguyen 13 , Sabina Signoretti 12 , Stefan Gradl 21 , Andreas Sutter 21 , Michael Jeffers 22 , Andreas Janzer 21 , Mark A Lehrman 14 , Lauren G Zacharias 3 , Thomas P Mathews 3 , Julie-Aurore Losman 4 , Timothy E Richardson 23 , Daniel P Cahill 24 , Ralph J DeBerardinis 25 , Keith L Ligon 26 , Lin Xu 27 , Peter Ly 9 , Nathalie Y R Agar 28 , Kalil G Abdullah 29 , Isaac S Harris 30 , William G Kaelin 31 , Samuel K McBrayer 32
Affiliation  

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH’s ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.



中文翻译:


从头合成嘧啶是 IDH 突变神经胶质瘤的一个可靶向脆弱性



影响异柠檬酸脱氢酶 (IDH) 的突变在神经胶质瘤、白血病和其他癌症中普遍存在。尽管突变 IDH 抑制剂对白血病有效,但它们在侵袭性神经胶质瘤中的活性似乎较低,这凸显了对替代治疗策略的需要。通过化学合成致死率筛选,我们发现 IDH1 突变型胶质瘤细胞对靶向嘧啶核苷酸从头合成途径中的酶的药物高度敏感,包括二氢乳清酸脱氢酶 (DHODH)。我们开发了突变 IDH1 驱动的星形细胞瘤的基因工程小鼠模型,并将其与多个患者衍生模型一起使用,以证明脑渗透性 DHODH 抑制剂 BAY 2402234 对 IDH 突变神经胶质瘤具有单一疗法功效。从机制上讲,这反映了神经胶质瘤细胞对从头嘧啶合成途径的绝对依赖,以及突变 IDH 在核苷酸池失衡时对 DNA 损伤敏感的能力。我们的工作概述了一种肿瘤选择性、生物标志物引导的治疗策略,该策略有望用于临床转化。

更新日期:2022-08-18
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