Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia

  • Cell Rep. 2026 Mar 28;45(4):117185. doi: 10.1016/j.celrep.2026.117185.
Léa Goupille  1 ,  Alexandre Boudet  2 ,  Laura Lauture  2 ,  Ambrine Sahal  2 ,  Guillaume Gautier-Renard  3 ,  Emeline Chu-Van  3 ,  Anvi Laetitia Nguyen  3 ,  Céline Chollet  3 ,  Coralie Alcazar  1 ,  Isabelle Bernard  4 ,  François Vergez  5 ,  Véronique de Mas  5 ,  Christian Récher  6 ,  Tony Kaoma  7 ,  Paolo Gallipoli  8 ,  Vilma Dembitz  9 ,  Irene Basili  10 ,  Flavia Bernardi  11 ,  Olivier Ayrault  11 ,  Carine Joffre  2 ,  Florence Castelli  3 ,  Benoit Colsch  3 ,  Nathalie Bourgès-Abella  12 ,  Fanny Granat  13 ,  Jean-Emmanuel Sarry  14
Affiliations
  • 1. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France; Université de Toulouse, CREFRE, Inserm, UPS, ENVT, Toulouse, France.
  • 2. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France.
  • 3. Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (MTS), MetaboHUB, Gif sur Yvette 91191, France.
  • 4. Université de Toulouse, CREFRE, Inserm, UPS, ENVT, Toulouse, France.
  • 5. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France; Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Laboratoire d'Hématologie, Toulouse, France.
  • 6. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France; Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Service d'Hématologie, Toulouse, France.
  • 7. Bioinformatics Platform, Department of Medical Informatics, Luxembourg Institute of Health, Strassen 1445, Luxembourg.
  • 8. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
  • 9. Department of Physiology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 3, Zagreb 10 000, Croatia.
  • 10. Institut Curie, PSL Research University, Inserm U1330 / CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Paris, France; Institut Curie, Université Paris-Saclay, Inserm U1330 / CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Orsay, France; Instituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome 00161, Italy.
  • 11. Institut Curie, PSL Research University, Inserm U1330 / CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Paris, France; Institut Curie, Université Paris-Saclay, Inserm U1330 / CNRS EMR 8001. Children's Oncology Research Unit (CONCERT), Orsay, France.
  • 12. Université de Toulouse, CREFRE, Inserm, UPS, ENVT, Toulouse, France; Université de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France.
  • 13. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France; Université de Toulouse, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France. Electronic address: [email protected].
  • 14. Université de Toulouse, Centre de Recherches en Cancérologie de Toulouse, Inserm U1037, CNRS U5077, Toulouse, France; LabEx Toucan, Toulouse, France; Équipe Labellisée Ligue Nationale Contre le Cancer 2026, Toulouse, France; Université de Toulouse, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. Electronic address: [email protected].
PMID: 41904949 DOI: 10.1016/j.celrep.2026.117185
Abstract

FMS-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) are associated with adverse prognosis. FLT3 inhibitors (FLT3i) improve therapeutic response; however, diverse resistance mechanisms, such as adaptations in lipid metabolism, have been identified. We hypothesized that a lipid-rich ketogenic diet (KD) might alter both host and tumoral lipid metabolism, enhancing responses to FLT3i. In FLT3-mutated AML mouse models, 3 weeks of lard- or plant-based KD improved the efficacy of FLT3i by 2-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver, and AML cells and also induced a polyunsaturated fatty acid:monounsaturated fatty acid (PUFA:MUFA) imbalance. KD impacted pentoses, hexoses, and amino acid metabolism, enhancing sugar phosphates and Vitamins in the host. Mechanistically, KD rewired anabolism toward fatty acid oxidation and glycine-utilizing pathways, modulated the expression of FLT3 signaling pathways and lipid biosynthesis, and promoted tumor cell differentiation. In conclusion, this study shows that KD reduces FLT3i resistance, offering a promising therapeutic solution.

Keywords
CP: cancer; CP: metabolism; FLT3-ITD mutations; acute myeloid leukemia; ketogenic diet; metabolism; therapy resistance.
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