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https://hdl.handle.net/2440/137435
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Type: | Journal article |
Title: | Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability |
Author: | Thomas, D. Wu, M. Nakauchi, Y. Zheng, M. Thompson-Peach, C.A. Lim, K. Landberg, N. Köhnke, T. Robinson, N. Kaur, S. Kutyna, M. Stafford, M. Hiwase, D. Reinisch, A. Peltz, G. Majeti, R. |
Citation: | Cancer Discovery, 2023; 13(2):496-515 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2023 |
ISSN: | 2159-8274 2159-8290 |
Statement of Responsibility: | Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe A.L. Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majeti |
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 a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to 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+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax. |
Keywords: | Humans Glutarates Isocitrate Dehydrogenase Enzyme Inhibitors Mutation Leukemia, Myeloid, Acute |
Rights: | ©2022 The Authors; Published by the American Association for Cancer Research. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License . |
DOI: | 10.1158/2159-8290.cd-21-0218 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1182564 http://purl.org/au-research/grants/nhmrc/1184485 |
Published version: | http://dx.doi.org/10.1158/2159-8290.cd-21-0218 |
Appears in Collections: | Medicine publications |
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hdl_137435.pdf | Published version | 16.62 MB | Adobe PDF | View/Open |
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