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The implications of IDH mutations for cancer development and therapy
Nature Reviews Clinical Oncology ( IF 78.8 ) Pub Date : 2021-06-15 , DOI: 10.1038/s41571-021-00521-0
Christopher J Pirozzi 1, 2 , Hai Yan 1, 2
Affiliation  

Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.



中文翻译:

IDH突变对癌症发展和治疗的影响

编码异柠檬酸脱氢酶(分别为IDH1IDH2 统称为IDH)的细胞质和线粒体形式的基因突变经常在各种来源的癌症中检测到,包括但不限于急性髓性白血病(20%)、胆管癌( 20%)、软骨肉瘤 (80%) 和神经胶质瘤 (80%)。在所有情况下,突变酶的新变体活性导致肿瘤代谢物D -2-羟基戊二酸的产生,其具有显着的细胞自主和非细胞自主效应。IDH的广泛影响表观遗传、分化和代谢程序的突变,加上它们在各种癌症类型中的高患病率、肿瘤发生的早期存在和肿瘤细胞中的均匀表达,使突变 IDH 成为理想的治疗靶点。在此,我们描述了当前对IDH突变的生物学理解以及突变 IDH 在各种相关癌症中的作用。我们还提供了有关靶向IDH突变癌症的各种方法的可用临床前和临床数据,并根据不同IDH突变癌症类型的潜在发病机制讨论治疗方法是否会趋同或取决于上下文。

更新日期:2021-06-15
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