A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations.
A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations.
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AZD1775靶向细胞周期检查点激酶Wee1，并通过p53依赖或不依赖的机制增强基因毒性药物的细胞毒性。在这里，我们报道AZD1775与组蛋白去乙酰化酶抑制剂（hdac，如Vorinostat）协同作用，阻断DNA损伤反应（DDR），杀死p53野生型或-缺陷型以及FLT3-ITD白血病细胞，这与明显的Wee1抑制和cdc2/Cdk1 Y15磷酸化减少有关。同样，Wee1 shRNA敲除显著使细胞对HDACIs敏感。AZD1775诱导Chk1激活，表现为Chk1 S296/S317/S345磷酸化显著增加，导致cdc2/Cdk1 T14磷酸化抑制，但这些代偿反应被hdac急剧消除。这伴随着过早的有丝分裂进入，多次有丝分裂异常，早期s期细胞的积累显示出增加的新复制DNA，最终导致强烈的DNA损伤和凋亡。该方案对携带野生型或突变型p53以及各种ngs定义突变的患者源性AML细胞有效。原始CD34+/CD123+/CD38−群体富集白血病起始祖细胞，而不是正常的CD34+造血细胞，对该方案高度敏感。最后，AZD1775与伏立诺他联合用于AML小鼠异种移植可显著降低肿瘤负荷，延长动物生存期。结合Wee1和HDACI抑制的策略值得在预后不良遗传畸变的AML中进一步研究。
AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs e.g., Vorinostat), which interrupt the DNA damage response (DDR), to kill p53-wild type or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knock-down significantly sensitized cells to HDACIs. While AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities, and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived AML cells harboring either wild type or mutant p53, and various NGS-defined mutations. Primitive CD34+/CD123+/CD38− populations enriched for leukemia-initiating progenitors, but not normal CD34+ hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations.
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DOI：
10.1083/jcb.200905059
发表时间：
2010-03-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Beck H;Nähse V;Larsen MS;Groth P;Clancy T;Lees M;Jørgensen M;Helleday T;Syljuåsen RG;Sørensen CS
通讯作者：
Sørensen CS
影响因子：
5.7
作者：
Dai Y;Chen S;Kmieciak M;Zhou L;Lin H;Pei XY;Grant S
通讯作者：
Grant S
影响因子：
5.7
作者：
Batey MA;Zhao Y;Kyle S;Richardson C;Slade A;Martin NM;Lau A;Newell DR;Curtin NJ
通讯作者：
Curtin NJ
影响因子：
11.5
作者：
Eriksson, David;Loefroth, Per-Olov;Stigbrand, Torgny
通讯作者：
Stigbrand, Torgny
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.