Parker Seth J, Metallo Christian M
Department of Bioengineering, University of California, San Diego, La Jolla, California, United States.
Department of Bioengineering, University of California, San Diego, La Jolla, California, United States; Moores Cancer Center, University of California, San Diego, La Jolla, California, United States.
Pharmacol Ther. 2015 Aug;152:54-62. doi: 10.1016/j.pharmthera.2015.05.003. Epub 2015 May 5.
Specific point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in a variety of cancers, including acute myeloid leukemia (AML), low-grade gliomas, and chondrosarcomas. These mutations inactivate wild-type enzymatic activity and convey neomorphic function to produce d-2-hydroxyglutarate (d-2HG), which accumulates at millimolar levels within tumors. d-2HG can impact α-ketoglutarate-dependent dioxygenase activity and subsequently affect various cellular functions in these cancers. Inhibitors of the neomorphic activity of mutant IDH1 and IDH2 are currently in Phase I/II clinical trials for both solid and blood tumors. As IDH1 and IDH2 represent key enzymes within the tricarboxylic acid (TCA) cycle, mutations have significant impact on intermediary metabolism. The loss of some wild-type metabolic activity is an important, potentially deleterious and therapeutically exploitable consequence of oncogenic IDH mutations and requires continued investigation in the future. Here we review how IDH1 and IDH2 mutations influence cellular metabolism, epigenetics, and other biochemical functions, discussing these changes in the context of current efforts to therapeutically target cancers bearing these mutations.
异柠檬酸脱氢酶1和2（IDH1和IDH2）的特定点突变存在于多种癌症中，包括急性髓系白血病（AML）、低级别胶质瘤和软骨肉瘤。这些突变使野生型酶活性失活，并赋予新功能以产生d-2-羟基戊二酸（d-2HG），其在肿瘤内以毫摩尔水平积累。d-2HG可影响α-酮戊二酸依赖性双加氧酶活性，进而影响这些癌症中的各种细胞功能。突变型IDH1和IDH2新功能活性的抑制剂目前正在针对实体瘤和血液肿瘤进行I/II期临床试验。由于IDH1和IDH2是三羧酸（TCA）循环中的关键酶，突变对中间代谢有重大影响。一些野生型代谢活性的丧失是致癌性IDH突变的一个重要的、潜在有害且可用于治疗的后果，未来需要继续进行研究。在此，我们综述IDH1和IDH2突变如何影响细胞代谢、表观遗传学和其他生化功能，并在当前针对携带这些突变的癌症进行治疗靶点研究的背景下讨论这些变化。
