ArticleCancer discovery2023
Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 56 citations in OpenAlex.
- Recent trends in research on the role of cholesterol in leukemia: a bibliometric and visualization study.Frontiers in immunology · 2025Pooled it
- Fatty acids metabolic reprogramming and tumor microenvironment in pancreatic cancer: targeting pathways.Clinical and experimental medicine · 2026Review
- Targeting chordoma via an isocitrate dehydrogenase-1-dependent susceptibility to redox metabolism.Acta neuropathologica · 2026Article
- Autopalmitoylation of IDH1-R132H regulates its neomorphic activity in cancer cells.Nature chemical biology · 2026Article
- Article
- TAF15-mediated m5C modification of MTHFD2 RNA reveals a novel therapeutic target for IDH mutant gliomas.Biomarker research · 2026Article
- Discovery of chirally dependent protein modifications by D- and L-2-hydroxyglutarates.Nature chemistry · 2026Article
- Predicting isocitrate dehydrogenase mutation status in acute myeloid leukemia from gene expression profiles by machine learning.NAR genomics and bioinformatics · 2026Article
- c-Fos-driven metabolic switch of α-ketoglutarate orchestrates progression in prostate cancer.Cell death & disease · 2026Article
- Lipid metabolism reprogramming shapes the immune landscape in the tumor microenvironment.Cellular & molecular immunology · 2026Review
- Resistance to Targeted Therapy in AML: Current Challenges and Emerging Treatment Strategies.Journal of clinical medicine · 2026Review
- Metabolic reprogramming in cancer: dysregulation of glucose, lipid, and amino acid pathways and therapeutic opportunities.Molecular biomedicine · 2026Review
- Succinate dehydrogenase-deficient cancer cells have increased susceptibility to Ym155-induced DNA damage.Endocrine-related cancer · 2026Article
- Metformin induces ferroptosis associated with lipidomic remodeling in AML.Blood advances · 2026Article
- Therapeutic targeting of chromatin alterations in leukemia and solid tumors.International journal of cancer · 2026Review
- MCJ modulates mitochondrial ETC flux to promote lipid metabolism-driven enhancement of cell proliferation and migration.Cell death & disease · 2026Article
- MYC-Mediated Functional Manifestation of IDH1 Mutations in Intrahepatic Cholangiocarcinoma Confers Sensitivity to (+)-JQ1.International journal of biological sciences · 2026Article
- Exploring Lipid Metabolic Reprogramming: Mechanistic Insights and Implications for Tumor Radiotherapy.International journal of biological sciences · 2026Review
- Bone marrow microenvironment reprogramming in myelodysplastic neoplasms: from pathological mechanisms to targeted therapeutic strategies.Frontiers in immunology · 2026Review
- Mediterranean Pattern Diet in Multiple Sclerosis: A Review Focusing on Immunometabolites.Current neuropharmacology · 2026Review
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Authors and funding
16 authors at 4 institutions in 4 countries.
Funding
Abstract
Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme [acetyl CoA carboxylase 1 (ACC1)] as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified an mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to b-oxidation indicating reprogramming of metabolism toward a reliance on fatty acids. Compared with mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ hematopoietic stem/progenitor cells or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in the growth inhibition of mIDH1 cancers not reversible by ivosidenib. Critically, the pharmacologic targeting of ACC1 improved the sensitivity of mIDH1 AML to venetoclax. SIGNIFICANCE: Oncogenic mutations in both IDH1 and IDH2 produce 2-hydroxyglutarate and are generally considered equivalent in terms of pathogenesis and targeting. Using comprehensive metabolomic analysis, we demonstrate unexpected metabolic differences in fatty acid metabolism between mutant IDH1 and IDH2 in patient samples with targetable metabolic interventions. See related commentary by Robinson and Levine, p. 266. This article is highlighted in the In This Issue feature, p. 247.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.