酪氨酸激酶抑制剂 FMS 样酪氨酸激酶 3 和 WEE1 在急性髓系白血病细胞中协同诱导细胞凋亡和 DNA 损伤。
Inhibitors of the tyrosine kinases FMS-like tyrosine kinase-3 and WEE1 induce apoptosis and DNA damage synergistically in acute myeloid leukemia cells.
发表日期：2024 Jul 05
作者：
Christoph Hieber, Al-Hassan M Mustafa, Sarah Neuroth, Sven Henninger, Hans-Peter Wollscheid, Joanna Zabkiewicz, Michelle Lazenby, Caroline Alvares, Siavosh Mahboobi, Falk Butter, Walburgis Brenner, Matthias Bros, Oliver H Krämer
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
具有内部串联重复的高活性 FMS 样受体酪氨酸激酶 3 突变体 (FLT3-ITD) 是侵袭性急性髓性白血病 (AML) 的常见驱动突变。 FLT3 抑制剂在合理设计的共治疗方案中产生了有希望的结果。由于 FLT3-ITD 调节 DNA 复制和 DNA 修复，因此有效的抗白血病策略可能依赖于 FLT3-ITD 的联合抑制以及细胞周期进程和 DNA 完整性的调节剂。其中包括控制细胞周期进程、核苷酸合成和 DNA 复制起点激发的 WEE1 激酶。我们研究了 FLT3 和 WEE1 的药理抑制如何影响 AML 细胞系和原代 AML 细胞的存活和基因组完整性。我们发现，FLT3 和 WEE1 的有前途的临床级和临床前抑制剂可协同触发表达 FLT3-ITD 的白血病细胞凋亡。在此过程之前，单链和双链 DNA 损伤会累积。基于质谱的蛋白质组学分析表明，FLT3-ITD 和 WEE1 维持核糖核苷酸还原酶亚基 RRM2 的表达，为 DNA 复制提供 dNTP。与 FLT3-ITD 对白血病细胞的强烈促凋亡作用不同，FLT3 和 WEE1 抑制剂不会损害健康的人类血细胞和小鼠造血干细胞。因此，FLT3-ITD 和 WEE1 的药理学抑制可能成为一种改进的、合理设计的治疗选择。版权所有 © 2024 作者。由 Elsevier Masson SAS 出版。保留所有权利。
Hyperactive FMS-like receptor tyrosine kinase-3 mutants with internal tandem duplications (FLT3-ITD) are frequent driver mutations of aggressive acute myeloid leukemia (AML). Inhibitors of FLT3 produce promising results in rationally designed cotreatment schemes. Since FLT3-ITD modulates DNA replication and DNA repair, valid anti-leukemia strategies could rely on a combined inhibition of FLT3-ITD and regulators of cell cycle progression and DNA integrity. These include the WEE1 kinase which controls cell cycle progression, nucleotide synthesis, and DNA replication origin firing. We investigated how pharmacological inhibition of FLT3 and WEE1 affected the survival and genomic integrity of AML cell lines and primary AML cells. We reveal that promising clinical grade and preclinical inhibitors of FLT3 and WEE1 synergistically trigger apoptosis in leukemic cells that express FLT3-ITD. An accumulation of single and double strand DNA damage precedes this process. Mass spectrometry-based proteomic analyses show that FLT3-ITD and WEE1 sustain the expression of the ribonucleotide reductase subunit RRM2, which provides dNTPs for DNA replication. Unlike their strong pro-apoptotic effects on leukemia cells with FLT3-ITD, inhibitors of FLT3 and WEE1 do not damage healthy human blood cells and murine hematopoietic stem cells. Thus, pharmacological inhibition of FLT3-ITD and WEE1 might become an improved, rationally designed therapeutic option.Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.