DHODH是PIK3CA突变结直肠癌中的合成致死靶点
DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.
摘要(中文译文)
癌细胞在致癌突变的驱动下获得独特的代谢和信号依赖。界定这些突变特异性依赖可为治疗提供机会。在此，我们将二氢乳清酸脱氢酶（DHODH）确定为PIK3CA突变型结直肠癌（CRC）中的选择性代谢依赖。DHODH通过促进尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）的生成，维持WDR77的O-GlcNAc糖基化及蛋白稳定性，从而维持PI3K-AKT信号传导。对DHODH的遗传学或药理学抑制可降低WDR77蛋白丰度、减少磷酸化AKT，并损害癌细胞的自我更新和肿瘤起始能力。补充尿苷可恢复WDR77和AKT信号，而敲低O-GlcNAc转移酶（OGT）则消除这一挽救效应，从而确立了一种依赖UDP、将嘧啶代谢与信号维持相联系的机制。使用DHODH抑制剂HL6处理可重现上述遗传学表型，并在异种移植、原位及患者来源的CRC模型中抑制肿瘤生长。本研究表明，蛋白稳定性的代谢调控是CRC中致癌基因特异性依赖的关键机制。
Abstract
Cancer cells acquire distinct metabolic and signaling dependencies driven by oncogenic mutations. Defining these mutation-specific liabilities can uncover therapeutic opportunities. Here, we identify dihydroorotate dehydrogenase (DHODH) as a selective metabolic dependency in PIK3CA-mutant colorectal cancer (CRC). DHODH sustains WDR77 O-GlcNAcylation and protein stability by promoting the generation of uridine diphosphate (UDP)-N-acetylglucosamine (UDP-GlcNAc), thereby maintaining PI3K-AKT signaling. Genetic or pharmacological inhibition of DHODH reduces WDR77 protein abundance, decreases phosphorylated AKT, and impairs cancer cell self-renewal and tumor initiation. Uridine supplementation restores WDR77 and AKT signaling, whereas O-GlcNAc transferase (OGT) depletion abrogates this rescue, establishing a UDP-dependent mechanism linking pyrimidine metabolism to signaling maintenance. Treatment with the DHODH inhibitor HL6 recapitulates the genetic phenotypes and suppresses tumor growth in xenograft, orthotopic, and patient-derived CRC models. This study demonstrates that the metabolic regulation of protein stability represents a critical mechanism underlying oncogene-specific dependencies in CRC.
如何引用
AMA
Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, et al. DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.. Cell reports. 2026; doi:10.1016/j.celrep.2026.117719.
APA
Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, et al (2026). DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.. Cell reports. https://doi.org/10.1016/j.celrep.2026.117719
GB/T 7714
Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, et al. DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.[J]. Cell reports, 2026 doi:10.1016/j.celrep.2026.117719.
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