Education and Research Centre, St. Vincent's University Hospital, Dublin, Ireland.
Cancer Biol Ther. 2013 Jun;14(6):537-45. doi: 10.4161/cbt.24349.
PARP inhibitors, both as monotherapy and in combination with cytotoxic drugs, are currently undergoing clinical trials in several different cancer types. In this investigation, we compared the antiproliferative activity of two PARP/putative PARP inhibitors, i.e., olaparib and iniparib, in a panel of 14 breast cancer cell lines (seven tripe-negative and seven non-triple-negative). In almost all cell lines investigated, olaparib was a more potent inhibitor of cell growth than iniparib. Inhibition by both drugs was cell line-dependent and independent of the molecular subtype status of the cells, i.e., whether cells were triple-negative or non-triple negative. Although the primary target of PARP inhibitors is PARP1, no significant association was found between baseline levels of PARP1 activity and inhibition with either agent. Similarly, no significant correlation was evident between sensitivity and levels of CDK1, BRCA1 or miR-182. Combined addition of olaparib and either the CDK1 inhibitor, RO-3306 or a pan HER inhibitor (neratinib, afatinib) resulted in superior growth inhibition to that obtained with olaparib alone. We conclude that olaparib, in contrast to iniparib, is a strong inhibitor of breast cancer cell growth and may have efficacy in breast cancer irrespective of its molecular subtype, i.e., whether HER2-positive, estrogen receptor (ER)-positive or triple-negative. Olaparib, in combination with a selective CDK1 inhibitor or a pan HER inhibitor, is a potential new approach for treating breast cancer.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂，无论是单药治疗还是与细胞毒性药物联合使用，目前都正在多种不同类型的癌症中进行临床试验。在这项研究中，我们比较了两种 PARP/假定 PARP 抑制剂，即奥拉帕尼和尼拉帕尼，在 14 种乳腺癌细胞系（7 种三阴性和 7 种非三阴性）中的抗增殖活性。在几乎所有研究的细胞系中，奥拉帕尼比尼拉帕尼更能抑制细胞生长。两种药物的抑制作用均依赖于细胞系，而与细胞的分子亚型状态无关，即细胞是三阴性还是非三阴性。尽管 PARP 抑制剂的主要靶标是 PARP1，但我们没有发现基线 PARP1 活性水平与两种药物中的任何一种的抑制作用之间存在显著相关性。同样，在敏感性和 CDK1、BRCA1 或 miR-182 水平之间也没有明显的相关性。奥拉帕尼与 CDK1 抑制剂 RO-3306 或 pan HER 抑制剂（奈拉替尼、阿法替尼）联合添加可导致生长抑制作用优于单独使用奥拉帕尼。我们得出的结论是，奥拉帕尼与尼拉帕尼不同，是一种强烈的乳腺癌细胞生长抑制剂，并且可能对乳腺癌具有疗效，而与乳腺癌的分子亚型无关，即无论 HER2 阳性、雌激素受体（ER）阳性还是三阴性。奥拉帕尼与选择性 CDK1 抑制剂或 pan HER 抑制剂联合使用，可能是治疗乳腺癌的一种新方法。
