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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Aurora激酶与CHEK1抑制剂在卵巢癌中的合成致死相互作用

卵巢癌的特征是 TP53 的频繁突变。这些肿瘤的同源重组修复基因也存在种系突变，因此它们依赖于 DNA 损伤检查点蛋白，如检查点激酶 1 (CHEK1) 来诱导 G2 期阻滞。在我们的研究中，通过使用计算机方法，我们确定了 CHEK1 和有丝分裂极光激酶 A (AURKA) 抑制剂之间的合成致死相互作用。基因表达分析用于鉴定相关生物学功能。OVCAR3、OVCAR8、IGROV1 和 SKOV3 用于增殖研究。Alisertib 被测试为 AURKA 抑制剂，LY2603618 被测试为 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质的分析。通过表面标志物的流式细胞术分析和球体形成分析来评估对干细胞特性的影响。基因表达分析和功能注释确定了一系列属于细胞周期的失调基因，包括 AURKA/B、TTK 激酶和 CHEK1。AURKA 和 CHEK1 分别在 8.7% 和 3.9% 的卵巢癌中被扩增。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 的表达与患者的不利结果有关。我们的数据描述了 CHEK1 和 AURKA 抑制剂之间的合成致死相互作用，可能转化为临床环境。摩尔癌症治疗; 16(11); 2552-62。©2017 AACR。