Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability

Thomas, Daniel ; Wu, Manhong ; Nakauchi, Yusuke ; Zheng, Ming ; Thompson-Peach, Chloe A L ; Lim, Kelly ; Landberg, Niklas LU orcid ; Köhnke, Thomas ; Robinson, Nirmal and Kaur, Satinder , et al. (2023) In Cancer Discovery 13(2). p.496-515
Abstract

UNLABELLED: 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... (More)

UNLABELLED: 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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
publishing date
type
Contribution to journal
publication status
published
keywords
Humans, Isocitrate Dehydrogenase, Glutarates/metabolism, Enzyme Inhibitors/pharmacology, Leukemia, Myeloid, Acute/drug therapy, Mutation
in
Cancer Discovery
volume
13
issue
2
pages
496 - 515
publisher
American Association for Cancer Research
external identifiers
  • scopus:85147458133
  • pmid:36355448
ISSN
2159-8274
DOI
10.1158/2159-8290.CD-21-0218
language
English
LU publication?
no
additional info
©2022 The Authors; Published by the American Association for Cancer Research.
id
8b595611-9fbf-49b0-acdf-aa11e57d1ec3
date added to LUP
2023-03-31 16:19:48
date last changed
2024-04-19 20:35:43
@article{8b595611-9fbf-49b0-acdf-aa11e57d1ec3,
  abstract     = {{<p>UNLABELLED: 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.</p><p>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.</p>}},
  author       = {{Thomas, Daniel and Wu, Manhong and Nakauchi, Yusuke and Zheng, Ming and Thompson-Peach, Chloe A L and Lim, Kelly and Landberg, Niklas and Köhnke, Thomas and Robinson, Nirmal and Kaur, Satinder and Kutyna, Monika and Stafford, Melissa and Hiwase, Devendra and Reinisch, Andreas and Peltz, Gary and Majeti, Ravindra}},
  issn         = {{2159-8274}},
  keywords     = {{Humans; Isocitrate Dehydrogenase; Glutarates/metabolism; Enzyme Inhibitors/pharmacology; Leukemia, Myeloid, Acute/drug therapy; Mutation}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{2}},
  pages        = {{496--515}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Cancer Discovery}},
  title        = {{Dysregulated Lipid Synthesis by Oncogenic IDH1 Mutation Is a Targetable Synthetic Lethal Vulnerability}},
  url          = {{http://dx.doi.org/10.1158/2159-8290.CD-21-0218}},
  doi          = {{10.1158/2159-8290.CD-21-0218}},
  volume       = {{13}},
  year         = {{2023}},
}