A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations

作者：Zhou, L.; Zhang, Y.; Chen, S.; Kmieciak, M.; Leng, Y.; Lin, H.; Rizzo, K. A.; Dumur, C. I.; Ferreira-Gonzalez, A.; Dai, Y.^*; Grant, S.

来源：Leukemia, 2015, 29(4): 807-818.

DOI：10.1038/leu.2014.296

• HISTONE DEACETYLASE INHIBITOR
• CYCLIN-DEPENDENT KINASES
• DNA-DAMAGING AGENTS
• MITOTIC CATASTROPHE
• THERAPEUTIC TARGET
• HOMOLOGOUS RECOMBINATION
• PRECLINICAL EVALUATION
• GENOMIC INSTABILITY
• CANCER-THERAPY
• TUMOR-CELLS

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.

• 出版日期2015-4
• 单位首都医科大学; 东北师范大学