biostudies-literatureLong JMinistry of Science and Technology of the People's Republic of ChinaNational Natural Science Foundation of China101286https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694671biostudies-literatureUnknown4(11)Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.Cell reports. MedicineA combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.PMC106946712021YFA110080081770187821701498172100482000143821001879144210631872842819201080058173000781830004Xiang RJiang JDong YSun YELong JHong DZhu HLiang AWang LMu LZhang WDing YLu HHu JLei YGao WChen XShen YWang ZfalseA combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.Internal tandem duplication mutations of the FMS-like tyrosine kinase-3 (FLT3-ITDs) occur in 25%-30% of patients with acute myeloid leukemia (AML) and are associated with dismal prognosis. Although FLT3 inhibitors have demonstrated initial clinical efficacy, the overall outcome of patients with FLT3-ITD AML remains poor, highlighting the urgency to develop more effective treatment strategies. In this study, we reveal that FLT3 inhibitors reduced protein stability of the anti-cancer protein p53, resulting in drug resistance. Blocking p53 degradation with proteasome inhibitors restores intracellular p53 protein levels and, in combination with FLT3-ITD inhibitors, shows superior therapeutic effects against FLT3-ITD AML in cells, mouse models, and patients. These data suggest that this combinatorial therapeutic approach may represent a promising strategy to target FLT3-ITD AML.2023-01-01T00:00:00Z2023 Nov2026-06-17T06:40:32.575Z2025-02-19T04:24:18.339ZS-EPMC106946713795121710.1016/j.xcrm.2023.101286