Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
Mol Cancer Ther. 2013 Jun;12(6):865-77. doi: 10.1158/1535-7163.MCT-12-0950. Epub 2013 Mar 19.
A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G2-M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencing of RAD51C in a resistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model. In summary, RAD51C-deficient cancer cells are highly sensitive to olaparib and offer preclinical proof-of-principle that RAD51C deficiency may be considered a biomarker for predicting the antitumor effects of olaparib.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂是一种针对 DNA 修复能力受损的癌症的合理设计的靶向治疗药物。RAD51C 是 RAD51 的同源物，在 DNA 损伤反应中具有重要作用。我们发现，使用微阵列分析，对新型口服 PARP 抑制剂奥拉帕尼敏感的细胞系 RAD51C 表达水平较低，因此我们假设 RAD51C 表达水平低可能会阻碍 DNA 修复过程，从而导致对奥拉帕尼的敏感性增加。与具有正常 RAD51C 表达水平的细胞相比，RAD51C 缺陷型癌细胞对奥拉帕尼更为敏感，并且通过诱导 G2-M 细胞周期阻滞和细胞凋亡导致更高比例的细胞死亡。在敏感细胞系中恢复 RAD51C 会减弱奥拉帕尼的敏感性。相比之下，在耐药细胞系中沉默 RAD51C 会增强对奥拉帕尼的敏感性，并且随着 RAD51C 表达的消除，RAD51 焦点的数量减少。我们还发现，由于表观遗传变化，癌细胞中 RAD51C 的表达下调，并且在一些胃癌组织中 RAD51C 的表达水平较低。此外，奥拉帕尼在异种移植模型中显著抑制 RAD51C 缺陷型肿瘤的生长。总之，RAD51C 缺陷型癌细胞对奥拉帕尼高度敏感，并提供了临床前的证据，证明 RAD51C 缺陷可能被认为是预测奥拉帕尼抗肿瘤作用的生物标志物。
