Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.

中文翻译：

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AG-636 揭示了恶性血液病中嘧啶饥饿的选择性脆弱性，AG-636 是一种新型的二氢乳清酸脱氢酶临床阶段抑制剂

靶向代谢途径的药物构成了标准肿瘤学治疗的支柱，尽管更好地了解不同的代谢依赖性可以指导更多基于原理的治疗方法。我们进行了一项化学生物学筛选，结果显示在血液学与实体瘤起源的癌细胞系中，对新型二氢乳清酸脱氢酶 (DHODH) 抑制剂 AG-636 的敏感性有很强的富集。差异 AG-636 活性转化为体内环境，在淋巴瘤模型中观察到完全的肿瘤消退。对尿苷可用性和对 AG-636 反应之间关系的剖析揭示了淋巴瘤和实体瘤细胞系在细胞外尿苷和 DHODH 抑制耗尽的情况下存活和生长的不同能力。代谢特征与无偏见的功能基因组和蛋白质组学筛选相结合，指出应对核苷酸压力的适应性机制有助于对 AG-636 的反应。这些发现支持在淋巴瘤和其他血液系统恶性肿瘤中靶向 DHODH，并提出旨在干扰 DNA 损伤反应途径的联合策略。