A combinatorial therapeutic approach to enhance FLT3-ITD AML treatment.

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.

• Authors: Jun Long, Xinjie Chen, Yan Shen, Yichen Lei, Lili Mu, Zhen Wang, Rufang Xiang, Wenhui Gao, Lining Wang, Ling Wang, Jieling Jiang, Wenjun Zhang, Huina Lu, Yan Dong, Yi Ding, Honghu Zhu, Dengli Hong, Yi Eve Sun, Jiong Hu, Aibin Liang
• Journal: Cell reports. Medicine (Cell Rep Med) Vol. 4 Issue 11 Pg. 101286 (11 21 2023) ISSN: 2666-3791 [Electronic] United States
• PMID: 37951217 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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