TY - JOUR
T1 - Targeting systemic and tumor metabolic balances with ketogenic diets enhance efficacy of therapy in FLT3-ITD acute myeloid leukemia
AU - Goupille, L.
AU - Boudet, Alexandre
AU - Lauture, Laura
AU - Sahal, Ambrine
AU - Gautier-Renard, Guillaume
AU - Chu-Van, Emeline
AU - Nguyen, Anvi Laetitia
AU - Chollet, Céline
AU - Alcazar, Coralie
AU - Bernard, Isabelle
AU - Vergez, François
AU - de Mas, Véronique
AU - Récher, Christian
AU - Kaoma, Tony
AU - Gallipoli, Paolo
AU - Dembitz, Vilma
AU - Basili, Irene
AU - Bernardi, Flavia
AU - Ayrault, Olivier
AU - Joffre, Carine
AU - Castelli, Florence
AU - Colsch, Benoit
AU - Bourgès-Abella, Nathalie
AU - Granat, Fanny
AU - Sarry, Jean Emmanuel
N1 - Publisher Copyright:
© 2026 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
PY - 2026/3/28
Y1 - 2026/3/28
N2 - 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.
AB - 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.
KW - CP: cancer
KW - CP: metabolism
KW - FLT3-ITD mutations
KW - acute myeloid leukemia
KW - ketogenic diet
KW - metabolism
KW - therapy resistance
UR - https://www.scopus.com/pages/publications/105034667500
UR - https://pubmed.ncbi.nlm.nih.gov/41904949/
U2 - 10.1016/j.celrep.2026.117185
DO - 10.1016/j.celrep.2026.117185
M3 - Article
C2 - 41904949
AN - SCOPUS:105034667500
SN - 2639-1856
VL - 45
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 117185
ER -