4.6 Article

A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment

Journal

CELL REPORTS MEDICINE
Volume 4, Issue 11, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.xcrm.2023.101286

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FLT3 inhibitors reduce the stability of the anti-cancer protein p53, leading to drug resistance. Blocking p53 degradation with proteasome inhibitors restores p53 protein levels and, when combined with FLT3-ITD inhibitors, shows superior therapeutic effects, suggesting a promising treatment strategy.
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.

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