{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Long J"],"funding":["Ministry of Science and Technology of the People's Republic of China","National Natural Science Foundation of China"],"pagination":["101286"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10694671"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["4(11)"],"pubmed_abstract":["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."],"journal":["Cell reports. Medicine"],"pubmed_title":["A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment."],"pmcid":["PMC10694671"],"funding_grant_id":["2021YFA1100800","81770187","82170149","81721004","82000143","82100187","91442106","31872842","81920108005","81730007","81830004"],"pubmed_authors":["Xiang R","Jiang J","Dong Y","Sun YE","Long J","Hong D","Zhu H","Liang A","Wang L","Mu L","Zhang W","Ding Y","Lu H","Hu J","Lei Y","Gao W","Chen X","Shen Y","Wang Z"],"additional_accession":[]},"is_claimable":false,"name":"A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.","description":"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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Nov","modification":"2026-06-17T06:40:32.575Z","creation":"2025-02-19T04:24:18.339Z"},"accession":"S-EPMC10694671","cross_references":{"pubmed":["37951217"],"doi":["10.1016/j.xcrm.2023.101286"]}}