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Review
. 2021 Apr 26:11:644857.
doi: 10.3389/fonc.2021.644857. eCollection 2021.

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

Jinxiu Guo  1   2 , Ruyue Zhang  1   2 , Zhe Yang  1   2 , Zhenfeng Duan  1   2 , Detao Yin  3 , Yubing Zhou  1   2
Affiliations
Review

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

Jinxiu Guo et al. Front Oncol. .

Abstract

Isocitrate dehydrogenase (IDH) is a key metabolic enzyme catalyzing the interconversion of isocitrate to α-ketoglutarate (α-KG). Mutations in IDH lead to loss of normal enzymatic activity and gain of neomorphic activity that irreversibly converts α-KG to 2-hydroxyglutarate (2-HG), which can competitively inhibit a-KG-dependent enzymes, subsequently induces cell metabolic reprograming, inhibits cell differentiation, and initiates cell tumorigenesis. Encouragingly, this phenomenon can be reversed by specific small molecule inhibitors of IDH mutation. At present, small molecular inhibitors of IDH1 and IDH2 mutant have been developed, and promising progress has been made in preclinical and clinical development, showing encouraging results in patients with IDH2 mutant cancers. This review will focus on the biological roles of IDH2 mutation in tumorigenesis, and provide a proof-of-principle for the development and application of IDH2 mutant inhibitors for human cancer treatment.

Keywords: 2-HG; IDH2 inhibitors; IDH2 mutation; cancer metabolism; cancers.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The roles of IDHs in cancer metabolism. Mutation of either IDH1 or IDH2 imparts a neomorphic enzymatic activity upon the encoded enzymes resulting in the ability to convert α-ketoglutarate (α-KG) into the oncometabolite 2-hydroxyglutarate (2-HG), and simultaneously converts NADPH to NADP+.
Figure 2
Figure 2
The molecular pathways of IDH mutations in tumorigenesis. 2-hydroxyglutarate competitively inhibits multiple α-ketoglutarate dependent dioxygenases, thereby causing widespread epigenetic changes that result in a global dysregulation of gene expression. 2-HG inhibits prolyl hydroxylases (PHD) and increases HIF-1α stabilization and result in impairment of collagen maturation. 2-HG can promote apoptosis by inhibiting cytochrome c oxidase (COX), and associate with tumor microenvironment.
Figure 3
Figure 3
IDH2 mutations in human cancers.
Figure 4
Figure 4
The chemical structures of currently developed inhibitors targeting IDH2 mutations.
See this image and copyright information in PMC

References

    1. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell (2011) 144(5):646–74. 10.1016/j.cell.2011.02.013 - DOI - PubMed
    1. Nagarajan A, Malvi P, Wajapeyee N. Oncogene-Directed Alterations in Cancer Cell Metabolism. Trends Cancer (2016) 2(7):365–77. 10.1016/j.trecan.2016.06.002 - DOI - PMC - PubMed
    1. Martinez-Outschoorn UE, Peiris-Pagés M, Pestell RG, Sotgia F, Lisanti MP. Cancer Metabolism: A Therapeutic Perspective. Nat Rev Clin Oncol (2017) 14(1):11–31. 10.1038/nrclinonc.2016.60 - DOI - PubMed
    1. Nowicki S, Gottlieb E. Oncometabolites: Tailoring Our Genes. FEBS J (2015) 282(15):2796–805. 10.1111/febs.13295 - DOI - PMC - PubMed
    1. Bhargava R, Florea AV, Pelmus M, Jones MW, Bonaventura M, Wald A, et al. Breast Tumor Resembling Tall Cell Variant of Papillary Thyroid Carcinoma: A Solid Papillary Neoplasm With Characteristic Immunohistochemical Profile and Few Recurrent Mutations. Am J Clin Pathol (2017) 147(4):399–410. 10.1093/ajcp/aqx016 - DOI - PubMed