Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

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Publication Details

Journal
Leukemia
Published
2024-08-26
DOI
https://doi.org/10.1038/s41375-024-02390-9
Citations
16
Primary Topic
Cancer, Lipids, and Metabolism
Type
article
Field-Weighted Citation Impact
4.56

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article

Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation

Sophie C. James, Michael J. Austin, Jérôme Tamburini, Mariia Yuneva et al.
16 citations
Leukemia
Cancer, Lipids, and Metabolism
4.56
article

Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation

Sophie C. James, Michael J. Austin, Jérôme Tamburini, Mariia Yuneva, Keith Woodley, Jan Jacob Schuringa, Findlay Bewicke‐Copley, Paolo Gallipoli, Andrew J. Finch, Juerg Schwaller, Emeline Boët, Vilma Dembitz, Lydia M. Wang, Pedro R. Cutillas, Richard Burt, Alex von Kriegsheim, Jozef Durko, Hannah Lawson, Ana Rio‐Machín, Jean‐Emmanuel Sarry, Lori Hazlehurst, Kamil R. Kranc, Sirisha Natani, Joana Campos, Lieve Oudejans, Pedro Casado, Bela G. Patel, Diego A. Pereira‐Martins, Aoife M. S. Magee, Céline Philippe, Kevin Rouault‐Pierre, Jude Fitzgibbon, Barrie Peck, Giovanny Rodriguez Blanco, Samantha Atkinson, John A. Copland
article en
16 citations

Abstract

Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients' outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

LeukemiaVol. 38(11)
University of Geneva (CH), Centre National de la Recherche Scientifique (FR), University Medical Center Groningen (NL), Institute of Cancer Research (GB), Inserm (FR), Queen Mary University of London (GB), University of Groningen (NL), Université Fédérale de Toulouse Midi-Pyrénées (FR), University of Zagreb (HR), University of Basel (CH), The Francis Crick Institute (GB), Jacksonville College (US), Edinburgh College (GB), Centre de Recherches en Cancérologie de Toulouse (FR), Oncogenesis Stress Signaling (FR), La Ligue Contre le Cancer (FR), University Children’s Hospital Basel (CH), Hospital Universitario Fundación Jiménez Díaz (ES), Modulation Therapeutics (United States) (US), Mayo Clinic in Florida (US), Swiss Cancer Center Léman (CH), Imperial College London (GB), Université de Rennes (FR), Universidad Autónoma de Madrid (ES), University of Edinburgh (GB)
National Science Foundation, Lady Tata Memorial Trust, Cancer Research UK, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Medical Research Council
Openalex Percentile: Top 4%
Cancer, Lipids, and Metabolism
4.56
DOIOpen Access PDFOpenAlex
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