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

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, three weeks of lard- or plant-based KD improved efficacy of FLT3i by two-fold reduction of engraftment and tumor burden. KD increased ketone bodies and lipid accumulation in plasma, liver and AML cells, and also induced a PUFA:MUFA imbalance. KD impacted pentoses, hexoses and amino acid metabolism, enhancing sugar phosphates and vitamins in host. Mechanistically, KD rewired anabolism towards 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. Overall design: CLDX model with MOLM14 cell engraftment treated with ketogenic diet versus standard diet (3 weeks) and gilteritinib versus vehicle (1 week); Dissection liver and bone marrow.