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首页> 外文期刊>Cell cycle >The contribution of DNA replication stress marked by high-intensity, pan-nuclear gamma H2AX staining to chemosensitization by CHK1 and WEE1 inhibitors
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The contribution of DNA replication stress marked by high-intensity, pan-nuclear gamma H2AX staining to chemosensitization by CHK1 and WEE1 inhibitors

机译：通过CHK1和WEE1抑制剂对高强度，泛核γH2AX染色的DNA复制应力标志的贡献

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Small molecule inhibitors of the checkpoint proteins CHK1 and WEE1 are currently in clinical development in combination with the antimetabolite gemcitabine. It is unclear, however, if there is a therapeutic advantage to CHK1 vs. WEE1 inhibition for chemosensitization. The goals of this study were to directly compare the relative efficacies of the CHK1 inhibitor MK8776 and the WEE1 inhibitor AZD1775 to sensitize pancreatic cancer cell lines to gemcitabine and to identify pharmacodynamic biomarkers predictive of chemosensitization. Cells treated with gemcitabine and either MK8776 or AZD1775 were first assessed for clonogenic survival. With the exception of the homologous recombination-defective Capan1 cells, which were relatively insensitive to MK8776, we found that these cell lines were similarly sensitized to gemcitabine by CHK1 or WEE1 inhibition. The abilities of either the CDK1/2 inhibitor roscovitine or exogenous nucleosides to prevent MK8776 or AZD1775-mediated chemosensitization, however, were both inhibitor-dependent and variable among cell lines. Given the importance of DNA replication stress to gemcitabine chemosensitization, we next assessed high-intensity, pan-nuclear gamma H2AX staining as a pharmacodynamic marker for sensitization. In contrast to total gamma H2AX, aberrant mitotic entry or sub-G1 DNA content, high-intensity gamma H2AX staining correlated with chemosensitization by either MK8776 or AZD1775 (R-2 0.83 - 0.53). In summary, we found that MK8776 and AZD1775 sensitize to gemcitabine with similar efficacy. Furthermore, our results suggest that the effects of CHK1 and WEE1 inhibition on gemcitabine-mediated replication stress best predict chemosensitization and support the use of high-intensity or pan-nuclear gamma H2AX staining as a marker for therapeutic response.
机译：检查点蛋白CHK1和WEE1的小分子抑制剂目前与抗体标签吉三滨组合的临床开发。然而，如果对CHK1与CHK1对化学敏化的抑制存在治疗优势，则尚不清楚。该研究的目标是直接比较CHK1抑制剂MK8776和WEE1抑制剂AZD1775的相对效果，使胰腺癌细胞系敏化到吉西他滨并鉴定预测化学敏化的药效生物标志物。首先评估用吉西他滨和MK8776或AZD1775处理的细胞用于克隆灭性存活。除了对MK8776相对不敏感的同源重组缺陷的Capan1细胞外，我们发现这些细胞系通过CHK1或WEE1抑制与吉西他滨类似敏感。然而，CDK1 / 2抑制剂Roscovitine或外源核苷以防止MK8776或AZD1775介导的化学敏化的能力在细胞系中依赖于抑制剂和可变。鉴于DNA复制应激对吉西他滨化学敏化的重要性，我们下次评估了高强度，泛核γH2AX染色作为敏化的药效记录。与总γH2AX，异常有丝分裂或亚g1 DNA含量，高强度γH2AX染色与MK8776或AZD1775的化学敏化相关（R-2 0.83-0.53）。总之，我们发现MK8776和AZD1775对吉西他滨具有相似的效力。此外，我们的结果表明，CHK1和WEE1抑制对吉西他滨介导的复制应力的影响最佳预测化学敏感性，并支持使用高强度或泛核γH2AX染色作为治疗反应的标志物。

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