A 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...

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Detalles Bibliográficos
Autores principales: Long, Jun, Chen, Xinjie, Shen, Yan, Lei, Yichen, Mu, Lili, Wang, Zhen, Xiang, Rufang, Gao, Wenhui, Wang, Lining, Wang, Ling, Jiang, Jieling, Zhang, Wenjun, Lu, Huina, Dong, Yan, Ding, Yi, Zhu, Honghu, Hong, Dengli, Sun, Yi Eve, Hu, Jiong, Liang, Aibin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10694671/
https://www.ncbi.nlm.nih.gov/pubmed/37951217
http://dx.doi.org/10.1016/j.xcrm.2023.101286
Descripción
Sumario: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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