IDH1 and IDH2 mutations as novel therapeutic targets: current perspectives
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Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to α-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic cholangiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit α-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. Furthermore, D-2HG is a biomarker suitable for the detection of IDH1/2 mutations at diagnosis and predictive of the clinical response. Finally, mutant-IDH1/2 enzymes inhibitors have entered clinical trials for patients with IDH1/2 mutations and represent a novel drug class for targeted therapy.
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Several ongoing studies have started targeting IDH1/2 metabolic genes as selective targets for new anticancer therapeutics.
“Several ongoing studies have started targeting these IDH1/2 metabolic genes as selective targets for new anticancer therapeutics [43].”
From Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells (2018) · cites this paper as [43]
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- Authors
- de Botton, S., Mondesir, J., Willekens, C., & Touat, M.
- Affiliations
- Inserm (FR)
- Université Paris-Saclay (FR)
- Venue
- Journal of Blood Medicine
- Publisher
- Informa UK Limited
- Published
- 2016-09
- Volume
- Volume 7
- Pages
- 171-180
- ISSN
- 1179-2736 (ISSN-L)
- PMC
- PMC5015873
- OpenAlex
- W2510836133
- Cited by
- 220
- References
- 123
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 19 · 2023: 21 · 2022: 29 · 2021: 30 · 2020: 29 · 2019: 16 · 2018: 32 · 2017: 20 · 2016: 2
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Blood Medicine (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Dove Medical Press (Taylor and Francis Group) (submittedVersion, cc-by-nc)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- IDH1 mutation, IDH2 mutation, isocitrate dehydrogenase, D-2-hydroxyglutarate, oncometabolites, alpha-ketoglutarate-dependent dioxygenase, histone demethylation, DNA demethylation, epigenetic regulation, low-grade glioma, secondary glioblastoma, chondrosarcoma, intrahepatic cholangiocarcinoma, hematologic malignancies, IDH inhibitors, targeted therapy, biomarkers
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