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

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

  • Leukemia. 2024 Nov;38(11):2395-2409. doi: 10.1038/s41375-024-02390-9.
Vilma Dembitz 1 2,  Hannah Lawson 1 3,  Richard Burt 4 5,  Sirisha Natani 1,  Céline Philippe 1 6,  Sophie C James 1,  Samantha Atkinson 4 5,  Jozef Durko 1,  Lydia M Wang 1 3,  Joana Campos 1 3,  Aoife M S Magee 1,  Keith Woodley 1,  Michael J Austin 1,  Ana Rio-Machin 1 7,  Pedro Casado 8,  Findlay Bewicke-Copley 1 8,  Giovanny Rodriguez Blanco 9,  Diego Pereira-Martins 10,  Lieve Oudejans 10,  Emeline Boet 11 12,  Alex von Kriegsheim 9,  Juerg Schwaller 13,  Andrew J Finch 14,  Bela Patel 1,  Jean-Emmanuel Sarry 11 12,  Jerome Tamburini 15,  Jan Jacob Schuringa 10,  Lori Hazlehurst 16,  John A Copland Iii 17,  Mariia Yuneva 5,  Barrie Peck 14,  Pedro Cutillas 8,  Jude Fitzgibbon 8,  Kevin Rouault-Pierre 1,  Kamil Kranc 1 3,  Paolo Gallipoli 18
Affiliations

Affiliations

  • 1 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 2 Department of Physiology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
  • 3 The Institute of Cancer Research, London, UK.
  • 4 Division of Cell and Molecular Biology, Imperial College London, London, UK.
  • 5 Francis Crick Institute, London, UK.
  • 6 INSERM U1242, University of Rennes, Rennes, France.
  • 7 Experimental Hematology Lab, IIS-Fundación Jimenez Díaz, UAM, Madrid, Spain.
  • 8 Centre for Cancer Genomics & Computational Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 9 The University of Edinburgh MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • 10 Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • 11 Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm U1037, CNRS U5077, LabEx Toucan, Toulouse, France.
  • 12 Équipe labellisée Ligue Nationale Contre le Cancer 2023, Toulouse, France.
  • 13 University Children's Hospital and Department of Biomedicine (DBM), University of Basel, Basel, Switzerland.
  • 14 Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 15 Translational Research Centre in Onco-hematology, Faculty of Medicine, University of Geneva and Swiss Cancer Center Leman, Geneva, Switzerland.
  • 16 Modulation Therapeutics, Morgantown, WV, USA.
  • 17 Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
  • 18 Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. [email protected].
PMID: 39187579 DOI: 10.1038/s41375-024-02390-9
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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