Rocca Céline J, Soares Daniele G, Bouzid Hana, Henriques João A P, Larsen Annette K, Escargueil Alexandre E
a Laboratory of Cancer Biology and Therapeutics ; Centre de Recherche Saint-Antoine ; Paris , France.
Cell Cycle. 2015;14(13):2080-90. doi: 10.1080/15384101.2015.1042632.
Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to S23906, thereby providing a rationale for patient selection in clinical trials.
DNA靶向抗癌药物的修复是一个具有基础和临床研究意义的活跃领域。然而，大多数研究都集中在少数化合物上，这限制了我们对DNA修复和DNA损伤反应的理解。S23906是一种阿霉素衍生物，在实验模型中对实体瘤显示出强大的活性。S23906在小沟中形成大体积单功能DNA加合物，导致双链螺旋不稳定。我们现在报告，S23906诱导DNA双链断裂的形成，这些断裂通过同源重组（HR）而非非同源末端连接（NHEJ）修复进行处理。有趣的是，与其他HR缺陷细胞系相比，S23906处理的BRCA2缺陷细胞具有更高的敏感性，并且在野生型（wt）细胞中会出现S期积累，但在BRCA2缺陷细胞中则不会。最近，我们已经表明S23906诱导的S期停滞是由检查点激酶Chk1介导的。然而，其活化的磷酸化形式在wt和BRCA2缺陷细胞中均由S23906同等诱导，这可能表明BRCA2在Chk1下游发挥作用。因此，用7-羟基星状孢菌素（UCN-01）或AZD7762解除S期停滞会增强S23906在wt细胞中的细胞毒性活性，但在BRCA2缺陷细胞中则不会。总之，我们的研究结果表明，BRCA2缺陷细胞对S23906的显著敏感性是由于S期停滞缺陷和HR修复缺失。因此，尤其是那些参与HR的蛋白质（特别是BRCA2）存在缺陷的肿瘤，可能对S23906表现出更高的敏感性，从而为临床试验中的患者选择提供了理论依据。
