生物
异柠檬酸脱氢酶
IDH1
表观遗传学
IDH2型
癌症研究
癌基因
突变体
癌症
基因
遗传学
生物信息学
酶
细胞周期
生物化学
作者
Meng-Ju Wu,Lei Shi,Joshua Merritt,Andrew X. Zhu,Nabeel Bardeesy
出处
期刊:Hepatology
[Wiley]
日期:2022-03-19
卷期号:75 (5): 1322-1337
被引量:21
摘要
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are the most frequently mutated metabolic genes across human cancers. These hotspot gain-of-function mutations cause the IDH enzyme to aberrantly generate high levels of the oncometabolite, R-2-hydroxyglutarate, which competitively inhibits enzymes that regulate epigenetics, DNA repair, metabolism, and other processes. Among epithelial malignancies, IDH mutations are particularly common in intrahepatic cholangiocarcinoma (iCCA). Importantly, pharmacological inhibition of mutant IDH (mIDH) 1 delays progression of mIDH1 iCCA, indicating a role for this oncogene in tumor maintenance. However, not all patients receive clinical benefit, and those who do typically show stable disease rather than significant tumor regressions. The elucidation of the oncogenic functions of mIDH is needed to inform strategies that can more effectively harness mIDH as a therapeutic target. This review will discuss the biology of mIDH iCCA, including roles of mIDH in blocking cell differentiation programs and suppressing antitumor immunity, and the potential relevance of these effects to mIDH1-targeted therapy. We also cover opportunities for synthetic lethal therapeutic interactions that harness the altered cell state provoked by mIDH1 rather than inhibiting the mutant enzyme. Finally, we highlight key outstanding questions in the biology of this fascinating and incompletely understood oncogene.
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