Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS One. 2018 Nov 16;13(11):e0207399. doi: 10.1371/journal.pone.0207399. eCollection 2018.
PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor-resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂通过靶向 BRCA 突变和缺陷性同源重组修复（HRR）来治疗上皮性卵巢癌（EOC）。然而，用 PARP 抑制剂治疗 HRR 功能正常的 EOC 仍然具有挑战性。本研究旨在确定三嗪（核糖核苷酸还原酶抑制剂）、西地尼布（血管内皮生长因子受体酪氨酸激酶抑制剂）和 PARP 抑制剂奥拉帕利联合应用是否对 BRCA 野生型和 HRR 功能正常的 EOC 异种移植小鼠模型具有协同作用。此外，还研究了西地尼布增强三嗪和奥拉帕利疗效的机制。BRCA 野生型和 PARP 抑制剂耐药的 EOC 细胞系被皮下（s.c.）植入裸鼠或腹腔（i.p.）注射到 SCID-Beige 小鼠中。然后，通过 i.p. 给小鼠用奥拉帕利、西地尼布、三嗪、各种双药和三药组合进行治疗。通过测量裸鼠皮下肿瘤体积和 SCID-Beige 小鼠的腹围来评估治疗效果，以延迟肿瘤生长并延长小鼠的生存时间。在这两种异种移植小鼠模型中，三嗪、奥拉帕利和西地尼布的联合应用导致 BRCA 野生型 EOC 生长明显受到抑制，小鼠的生存时间显著延长，疗效大于任何双药组合和单药。此外，我们发现西地尼布阻断了生存和抗凋亡 AKT 信号，从而增强了三嗪和奥拉帕利对 BRCA 野生型 EOC 细胞的疗效。综上所述，我们的研究结果证明了一种原理验证方法，该联合方案有望治疗 BRCA 野生型和 PARP 抑制剂耐药的 EOC。
