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

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

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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