PDF(Pubmed)
Abstract：
Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.
摘要：
肿瘤细胞必须重新连接核苷酸合成以满足不受约束的增殖的需求。同时,它们表现出增加的活性氧（ROS）产生，这矛盾地破坏DNA和游离的脱氧核糖核苷三磷酸（dNTP）。这些代谢过程如何整合到燃料肿瘤发生中仍有待研究。MYC家族癌蛋白协调核苷酸合成和ROS生成以驱动多种癌症的发展。我们在此进行了基于聚类的定期间隔短回文重复（CRISPR）的靶向代谢基因的功能筛选，并将nudix水解酶1（NUDT1）鉴定为MYC驱动的依赖性。机械上,MYC协调两个平行作用的代谢途径的平衡，NADPH氧化酶4（NOX4）-ROS途径和Polo样激酶1（PLK1）-NUDT1核苷酸消毒途径。我们将LC-1-40描述为一种有效的，在体内消耗NUDT1的目标降解剂。LC-1-40的给药引起过度的核苷酸氧化，患者源性异种移植物的细胞毒性和治疗反应。因此，NUDT1的药理学靶向代表了一种可行的MYC驱动的代谢倾向。
