Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

Jinxiu Guo; Ruyue Zhang; Zhe Yang; Zhenfeng Duan; Detao Yin; Yubing Zhou

doi:10.3389/fonc.2021.644857

Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer

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

Authors

Jinxiu Guo^{1

2}, Ruyue Zhang^{1

2}, Zhe Yang^{1

2}, Zhenfeng Duan^{1

2}, Detao Yin³, Yubing Zhou^{1

2}

Affiliations

¹ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Henan Key Laboratory for Precision Clinical Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
³ Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

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.

Publication types

Review