1. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations
- Author
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Yun Dai, Kathryn A. Rizzo, Steven Grant, Maciej Kmieciak, Catherine I. Dumur, Yu Zhang, Liang Zhou, Andrea Ferreira-Gonzalez, Shuang Chen, Yun Leng, and Hui Lin
- Subjects
Cancer Research ,Cell cycle checkpoint ,Apoptosis ,Cell Cycle Proteins ,Hydroxamic Acids ,Mice ,checkpoint ,AML ,Myeloid Cells ,Phosphorylation ,WEE1 Inhibitor AZD1775 ,Vorinostat ,Gene Expression Regulation, Leukemic ,Nuclear Proteins ,Myeloid leukemia ,Drug Synergism ,Hematology ,Protein-Tyrosine Kinases ,Cell cycle ,cdc2/Cdk1 ,Cyclin-Dependent Kinases ,3. Good health ,Leukemia, Myeloid, Acute ,Leukemia ,Oncology ,Drug Therapy, Combination ,Signal Transduction ,medicine.drug ,Primary Cell Culture ,Wee1 inhibitor ,Chk1 ,DNA Fragmentation ,Biology ,Article ,HDAC inhibitor ,CDC2 Protein Kinase ,medicine ,Animals ,Humans ,CHEK1 ,Protein Kinase Inhibitors ,Cell Cycle Checkpoints ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Histone Deacetylase Inhibitors ,fms-Like Tyrosine Kinase 3 ,Checkpoint Kinase 1 ,Fms-Like Tyrosine Kinase 3 ,Cancer research ,Tumor Suppressor Protein p53 ,Protein Kinases - Abstract
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, for example, Vorinostat), which interrupt the DNA damage response, to kill p53-wild type (wt) or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knockdown significantly sensitized cells to HDACIs. Although 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 acute myelogenous leukemia (AML) cells harboring either wt or mutant p53 and various next-generation sequencing-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.
- Published
- 2014