Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Mol Cancer Ther. 2018 May;17(5):921-930. doi: 10.1158/1535-7163.MCT-17-0302. Epub 2018 Mar 28.
HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2 breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2 breast cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi), agents that target homologous recombination (HR)-deficient tumors, independent of a DNA repair deficiency. In this study, we investigated whether HER2 trastuzumab-resistant (TR) breast cancer cells were susceptible to PARPi and the mechanism behind PARPi induced cytotoxicity. We demonstrate that the PARPi ABT-888 (veliparib) decreased cell survival and tumor growth of HER2 TR breast cancer cells. PARP-1 siRNA confirmed that cytotoxicity was due, in part, to PARP-1 inhibition. Furthermore, PARP-1 silencing had variable effects on the expression of several NF-κB-regulated genes. In particular, silencing PARP-1 inhibited NF-κB activity and reduced p65 binding at the IL8 promoter, which resulted in a decrease in IL8 mRNA and protein expression. Our results provide insight in the potential mechanism by which PARPi induces cytotoxicity in HER2 breast cancer cells and support the testing of PARPi in patients with HER2 breast cancer resistant to trastuzumab. .
曲妥珠单抗等 HER2 靶向治疗提高了 HER2 阳性乳腺癌患者的生存率。然而，尽管采用了这些治疗方法，许多肿瘤最终还是会对这些治疗产生耐药性。我们实验室之前曾报道过一种意想不到的现象，即 HER2 阳性乳腺癌细胞对聚（ADP-核糖）聚合酶抑制剂（PARPi）敏感，而这些抑制剂针对同源重组（HR）缺陷型肿瘤，与 DNA 修复缺陷无关。在这项研究中，我们研究了 HER2 曲妥珠单抗耐药（TR）乳腺癌细胞是否对 PARPi 敏感，以及 PARPi 诱导细胞毒性的机制。我们证明 PARPi ABT-888（veliparib）可降低 HER2 TR 乳腺癌细胞的存活率和肿瘤生长。PARP-1 siRNA 证实细胞毒性部分归因于 PARP-1 抑制。此外，PARP-1 沉默对几种 NF-κB 调节基因的表达有不同的影响。特别是，沉默 PARP-1 抑制 NF-κB 活性并减少 p65 在 IL8 启动子上的结合，从而导致 IL8 mRNA 和蛋白表达减少。我们的结果提供了 PARPi 在 HER2 阳性乳腺癌细胞中诱导细胞毒性的潜在机制的见解，并支持在曲妥珠单抗耐药的 HER2 阳性乳腺癌患者中测试 PARPi。
