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 progn...

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Vydáno v:	Leukemia Ročník 38; číslo 11; s. 2395 - 2409
Hlavní autoři:	Dembitz, Vilma, Lawson, Hannah, Burt, Richard, Natani, Sirisha, Philippe, Céline, James, Sophie C., Atkinson, Samantha, Durko, Jozef, Wang, Lydia M., Campos, Joana, Magee, Aoife M. S., Woodley, Keith, Austin, Michael J., Rio-Machin, Ana, Casado, Pedro, Bewicke-Copley, Findlay, Rodriguez Blanco, Giovanny, Pereira-Martins, Diego, Oudejans, Lieve, Boet, Emeline, von Kriegsheim, Alex, Schwaller, Juerg, Finch, Andrew J., Patel, Bela, Sarry, Jean-Emmanuel, Tamburini, Jerome, Schuringa, Jan Jacob, Hazlehurst, Lori, Copland III, John A., Yuneva, Mariia, Peck, Barrie, Cutillas, Pedro, Fitzgibbon, Jude, Rouault-Pierre, Kevin, Kranc, Kamil, Gallipoli, Paolo
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 01.11.2024 Nature Publishing Group Springer Nature
Témata:	13/106 13/109 13/2 13/31 13/89 38 38/109 38/91 631/67/1990/283/1897 631/67/2327 64/60 692/308/153 82/58 82/80 Acute myeloid leukemia Animals Biobanks Biocompatibility Biology Biomarkers Biosynthesis Cancer Cancer Research Cancer therapies Cell culture Cell death Cell Line, Tumor Chemotherapy Chromatography Critical Care Medicine Damage detection Desaturase Desaturation DNA biosynthesis DNA damage DNA Damage - drug effects Enzyme Inhibitors - pharmacology Enzymes Experiments Fatty acids Fatty Acids - biosynthesis Fatty Acids - metabolism Glucose Hematology Humans Intensive Internal Medicine Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Life Sciences Medical prognosis Medical research Medicine Medicine & Public Health Metabolism Metabolites Mice Oncology Prognosis Stearoyl-CoA desaturase Stearoyl-CoA Desaturase - antagonists & inhibitors Stearoyl-CoA Desaturase - genetics Stearoyl-CoA Desaturase - metabolism Toxicity Xenograft Model Antitumor Assays
ISSN:	0887-6924, 1476-5551, 1476-5551
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/s41375-024-02390-9