A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment

Cell Rep Med. 2023 Nov 21;4(11):101286. doi: 10.1016/j.xcrm.2023.101286. Epub 2023 Nov 10.

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.

Keywords: FLT3 inhibitor; FLT3-ITD; MYC; USP10; acute myeloid leukemia; p53; proteasome inhibitor; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / metabolism
  • Mice
  • Mutation
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Treatment Outcome
  • Tumor Suppressor Protein p53* / genetics
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism
  • fms-Like Tyrosine Kinase 3 / therapeutic use

Substances

  • Tumor Suppressor Protein p53
  • Protein Kinase Inhibitors
  • fms-Like Tyrosine Kinase 3
  • FLT3 protein, human