IDH mutations in cancer and progress toward development of targeted therapeutics

Dang, L.; Yen, K.; Attar, E.C.

doi:10.1093/annonc/mdw013

Cited by 509Acute Myeloid Leukemia ResearchGlioma Diagnosis and TreatmentCancer, Hypoxia, and Metabolism

IDH mutations in cancer and progress toward development of targeted therapeutics

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Dang, L., Yen, K., Attar, E.C.·2016·Annals of Oncology

DOI 10.1093/annonc/mdw013

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Abstract

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, converting isocitrate to α-ketoglutarate (αKG).IDH1 and IDH2 mutations have been identified in multiple tumor types, including gliomas and myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here we provide an overview of the function of normal and mutated IDH, discuss the role of IDH mutations in tumorigenesis and progression and review the key clinical considerations when treating IDH-mutated tumors based on emerging clinical data from mutant IDH1/2 inhibitor trials. IDH1 and IDH2 mutations confer neomorphic activity in the mutant protein, resulting in the conversion of αKG to the oncometabolite, D-2-hydroxyglutarate (2-HG). The subsequent accumulation of 2-HG results in epigenetic dysregulation via inhibition of αKG-dependent histone and DNA demethylases, and a block in cellular differentiation. There is growing preclinical and clinical evidence suggesting that IDHmutations are involved in neoplasia. Furthermore, preclinical studies assessing small molecule inhibitors of mutant IDH1/2 enzymes have provided proof of concept that this approach decreases intracellular 2-HG levels, reverses epigenetic dysregulation and induces cellular differentiation. Phase I studies of mutant IDH inhibitors are currently ongoing in patients with IDH-mutant hematologic and solid tumors, with early data in hematologic tumors suggesting a manageable safety profile as well as clinical benefit, with a mechanism of action based on differentiation of malignant cells. Inhibition of mutant IDH shows promise as a treatment approach in hematologic malignancies, with further development ongoing in solid tumors and glioma. The mutant IDH inhibitors may have clinical utility both as single agents and in combination strategies that target additional oncogenic pathways.

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Recurrent somatic point mutations in IDH1 and IDH2 are found in a wide variety of cancers, including glioblastoma multiforme and acute myeloid leukemia.
“Recurrent somatic point mutations in the genes coding for isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) are found in a wide variety of cancers, including glioblastoma multiforme (GBM) (Yan et al., 2009) and acute myeloid leukemia (AML) (Dang et al., 2016; Mardis et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Dang et al., 2016

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Authors: Dang, L., Yen, K., & Attar, E. C.
Affiliations: Agios Pharmaceuticals (United States) (US)
Corresponding author: Attar, E.C.
ORCID: Dang, L.
Yen, K.
Attar, E.C.
Venue: Annals of Oncology
Publisher: Elsevier BV
Published: 2016-04
Volume: 27
Issue: 4
Pages: 599-608
ISSN: 0923-7534 (ISSN-L)
DOI: 10.1093/annonc/mdw013
OpenAlex: W2301066876
Cited by: 509
References: 104
Citations by year: 2026: 26 · 2025: 45 · 2024: 47 · 2023: 58 · 2022: 52 · 2021: 60 · 2020: 41 · 2019: 62 · 2018: 58 · 2017: 47 · 2016: 12
FWCI: 8.48
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1306 d)
Locations: Annals of Oncology (publishedVersion)
PubMed (publishedVersion)
HighWire Press Open Archive (submittedVersion)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: IDH1 mutation, IDH2 mutation, isocitrate dehydrogenase, 2-hydroxyglutarate, oncometabolites, epigenetic dysregulation, histone demethylation, DNA demethylation, cell differentiation, IDH inhibitors, glioma, acute myeloid leukemia, myelodysplastic syndrome, hematologic malignancies, solid tumors, targeted therapy
MeSH terms: Clinical Trials as Topic, Enzyme Inhibitors, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Leukemia, Myeloid, Acute, Molecular Targeted Therapy, Carcinogenesis

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IDH mutations in cancer and progress toward development of targeted therapeutics

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