SCD inhibition preferentially eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy Article Swipe
Vilma Dembitz
,
Hannah Lawson
,
Richard Burt
,
Céline Philippe
,
Sophie C. James
,
Samantha Atkinson
,
Jozef Durko
,
Lydia M. Wang
,
Joana Campos
,
Aoife M. S. Magee
,
Keith Woodley
,
Michael Austin
,
Ana Rio‐Machín
,
Pedro Casado
,
Findlay Bewicke‐Copley
,
Giovanny Rodriguez Blanco
,
Diego A. Pereira‐Martins
,
Lieve Oudejans
,
Emeline Boët
,
Alex von Kriegsheim
,
Juerg Schwaller
,
Andrew J. Finch
,
Bela Patel
,
Jean‐Emmanuel Sarry
,
Jérôme Tamburini
,
Jan Jacob Schuringa
,
Lori Hazlehurst
,
John A. Copland
,
Mariia Yuneva
,
Barrie Peck
,
Pedro R. Cutillas
,
Jude Fitzgibbon
,
Kevin Rouault‐Pierre
,
Kamil R. Kranc
,
Paolo Gallipoli
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.08.02.551656
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.08.02.551656
Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients’ outcome. These features should be ideally present in many patients independently of mutational background. Here we identify de novo fatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML models in vitro and in vivo . We use the novel clinical grade SCD inhibitor SSI-4 to show that SCD inhibition induces AML cell death via pleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. SSI-4 efficacy is enhanced by driving FA biosynthesis in vitro while stroma confers protective effects that extend to in vivo models. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. 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 therapeutic potential. One Sentence Summary SCD inhibition is toxic to AML cells with high rates of fatty acid desaturation and in combination with chemotherapy prolongs survival in murine AML models.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.08.02.551656
- https://www.biorxiv.org/content/biorxiv/early/2023/09/04/2023.08.02.551656.full.pdf
- OA Status
- green
- Cited By
- 1
- References
- 63
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4385602948
All OpenAlex metadata
Raw OpenAlex JSON
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- DOI
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https://doi.org/10.1101/2023.08.02.551656Digital Object Identifier
- Title
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SCD inhibition preferentially eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapyWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
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2023-08-05Full publication date if available
- Authors
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Vilma Dembitz, Hannah Lawson, Richard Burt, Céline Philippe, Sophie C. James, Samantha Atkinson, Jozef Durko, Lydia M. Wang, Joana Campos, Aoife M. S. Magee, Keith Woodley, Michael Austin, Ana Rio‐Machín, Pedro Casado, Findlay Bewicke‐Copley, Giovanny Rodriguez Blanco, Diego A. Pereira‐Martins, Lieve Oudejans, Emeline Boët, Alex von Kriegsheim, Juerg Schwaller, Andrew J. Finch, Bela Patel, Jean‐Emmanuel Sarry, Jérôme Tamburini, Jan Jacob Schuringa, Lori Hazlehurst, John A. Copland, Mariia Yuneva, Barrie Peck, Pedro R. Cutillas, Jude Fitzgibbon, Kevin Rouault‐Pierre, Kamil R. Kranc, Paolo GallipoliList of authors in order
- Landing page
-
https://doi.org/10.1101/2023.08.02.551656Publisher landing page
- PDF URL
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https://www.biorxiv.org/content/biorxiv/early/2023/09/04/2023.08.02.551656.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2023/09/04/2023.08.02.551656.full.pdfDirect OA link when available
- Concepts
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In vivo, Chemotherapy, Cancer research, In vitro, Biology, Pharmacology, Myeloid leukemia, Biochemistry, GeneticsTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2024: 1Per-year citation counts (last 5 years)
- References (count)
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63Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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