Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552–62. ©2017 AACR .

中文翻译：

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极光激酶和CHEK1抑制剂在卵巢癌之间的合成致死相互作用。

卵巢癌的特征是TP53处频繁发生突变。这些肿瘤还在同源重组修复基因处带有种系突变，因此它们依赖于DNA损伤的检查点蛋白，例如检查点激酶1（CHEK1）来诱导G2阻滞。在我们的研究中，通过使用计算机方法，我们确定了CHEK1与有丝分裂极光激酶A（AURKA）抑制剂之间的合成致死性相互作用。基因表达分析用于鉴定相关的生物学功能。OVCAR3，OVCAR8，IGROV1和SKOV3用于增殖研究。测试了Alisertib作为AURKA抑制剂，LY2603618作为CHEK1抑制剂。通过流式细胞术和蛋白质印迹分析进行细胞周期和细胞内介体的分析。通过表面标记的流式细胞术分析和球形成分析评估对干细胞特性的影响。基因表达分析和随后的功能注释识别出一系列属于细胞周期的失控基因，包括AURKA / B，TTK激酶和CHEK1。AURKA和CHEK1分别在8.7％和3.9％的卵巢癌中扩增。AURKA和CHEK1抑制剂在不同的细胞模型中显示出协同相互作用。alisertib和LY2603618的组合可引发细胞凋亡，减少干细胞数量，并增加紫杉烷和铂化合物的作用。最后，AURKA和CHEK1的表达与患者的不良结局有关。我们的数据描述了CHEK1和AURKA抑制剂之间的合成致死性相互作用，并可能转化为临床环境。分子癌疗法；16（11）; 2552–62。©2017 AACR。