Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation
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| Titel: | Stearoyl-CoA desaturase inhibition is toxic to acute myeloid leukemia displaying high levels of the de novo fatty acid biosynthesis and desaturation |
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| Autoren: | 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, Kriegsheim, Alex Von, Schwaller, Juerg, Finch, Andrew, Patel, Bela, Sarry, Jean-Emmanuel, Tamburini, Jérôme, Schuringa, Jan Jacob, Hazlehurst, Lori, Copland Iii, John A, Yuneva, Mariia, Peck, Barrie, Cutillas, Pedro, Fitzgibbon, Jude, Rouault-Pierre, Kevin, Kranc, Kamil, Gallipoli, Paolo |
| Weitere Verfasser: | Jonchère, Laurent |
| Quelle: | Leukemia |
| Verlagsinformationen: | Springer Science and Business Media LLC, 2024. |
| Publikationsjahr: | 2024 |
| Schlagwörter: | 0301 basic medicine, DNA Damage / drug effects, Article, Mice, 03 medical and health sciences, Leukemia, Myeloid, Acute / pathology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Humans, Animals, Enzyme Inhibitors, Fatty Acids / biosynthesis, 0303 health sciences, Stearoyl-CoA Desaturase / metabolism, Fatty Acids, Enzyme Inhibitors / pharmacology, Prognosis, Xenograft Model Antitumor Assays, 3. Good health, Leukemia, Myeloid, Acute, Fatty Acids / metabolism, Leukemia, Myeloid, Acute / metabolism, Stearoyl-CoA Desaturase / genetics, Leukemia, Myeloid, Acute / drug therapy, Stearoyl-CoA Desaturase, Stearoyl-CoA Desaturase / antagonists & inhibitors, DNA Damage |
| Beschreibung: | 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. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/s41375-024-02390-9 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/39187579 https://archive-ouverte.unige.ch/unige:183963 https://doi.org/10.1038/s41375-024-02390-9 https://urn.nsk.hr/urn:nbn:hr:105:358780 https://doi.org/10.1038/s41375-024-02390-9 |
| Rights: | CC BY |
| Dokumentencode: | edsair.doi.dedup.....9bbff744e94d5b07b458f21aca21d904 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | 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. |
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| ISSN: | 14765551 08876924 |
| DOI: | 10.1038/s41375-024-02390-9 |