FMS 样酪氨酸激酶 3 (FLT3-ITD) 的内部串联重复突变发生在 25%-30% 的急性髓系白血病 (AML) 患者中，并且与不良预后相关。尽管FLT3抑制剂已表现出初步的临床疗效，但FLT3-ITD AML患者的总体预后仍然较差，凸显了开发更有效治疗策略的紧迫性。在这项研究中，我们发现FLT3抑制剂降低了抗癌蛋白p53的蛋白稳定性，从而导致耐药性。用蛋白酶体抑制剂阻断 p53 降解可恢复细胞内 p53 蛋白水平，并与 FLT3-ITD 抑制剂联合使用，在细胞、小鼠模型和患者中显示出针对 FLT3-ITD AML 的卓越治疗效果。这些数据表明，这种组合治疗方法可能代表了一种针对 FLT3-ITD AML 的有前景的策略。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.