Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA; Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA 30322, United States of America.
Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, CT 06520, USA.
Gynecol Oncol. 2023 Mar;170:172-178. doi: 10.1016/j.ygyno.2023.01.015. Epub 2023 Jan 25.
Ovarian cancer (OC) is associated with the highest gynecologic cancer mortality. The development of novel, effective combinations of targeted therapeutics remains an unmet medical need. We evaluated the preclinical efficacy of the Poly (ADP-ribose) polymerase (PARP) inhibitor (olaparib) and the pan-ErbB inhibitor (neratinib) as single agents and in combination in ovarian cancer cell lines and xenografts with variable HER2 expression.
In vitro cell viability with olaparib, neratinib, and their combination was assessed using flow-cytometry based assays against a panel of OC primary cell lines with variable HER2 expression. Immunoblotting experiments were performed to elucidate the mechanism of activity and synergism. The in vivo antitumor activity of the olaparib/neratinib combination versus single agents was tested in HER2 positive xenograft OC models.
HER2 + OC cell lines demonstrated higher sensitivity to olaparib and neratinib when compared to HER2 negative tumors (i.e., IC: 2.06 ± 0.33 μM vs. 39.28 ± 30.51 μM, p = 0.0035 for olaparib and 19.42 ± 2.63 nM vs. 235.0 ± 165.0 nM, p = 0.0035 for neratinib). The combination of olaparib with neratinib was more potent when compared to single-agent olaparib or neratinib both in vitro and in vivo, and demonstrated synergy in all primary HER2 + OC models. Western blot experiments showed neratinib decreased pHER2/neu while increased Poly(ADP-ribose) (PAR) enzymatic activity; olaparib increased pHER2/Neu expression and blocked PAR activatio. Olaparib/neratinib in combination decreased both pHER2/Neu as well as PAR activation.
The combination of olaparib and neratinib is synergistic and endowed with remarkable preclinical activity against HER2+ ovarian cancers. This combination may represent a novel therapeutic option for ovarian cancer patients with HER2+, homologous recombination-proficient tumors resistant to chemotherapy.
卵巢癌（OC）与最高的妇科癌症死亡率相关。开发新型、有效的靶向治疗药物组合仍然是未满足的医疗需求。我们评估了聚（ADP-核糖）聚合酶（PARP）抑制剂（奥拉帕利）和泛-ErbB 抑制剂（奈拉替尼）作为单一药物以及在具有不同 HER2 表达的卵巢癌细胞系和异种移植模型中的临床前疗效。
使用针对具有不同 HER2 表达的 OC 原代细胞系的基于流式细胞术的测定法，评估奥拉帕利、奈拉替尼及其组合的体外细胞活力。进行免疫印迹实验以阐明活性和协同作用的机制。在 HER2 阳性异种移植 OC 模型中测试奥拉帕利/奈拉替尼组合与单药治疗的体内抗肿瘤活性。
与 HER2 阴性肿瘤相比，HER2 + OC 细胞系对奥拉帕利和奈拉替尼的敏感性更高（即 IC：2.06 ± 0.33 μM 与 39.28 ± 30.51 μM，p = 0.0035 对于奥拉帕利和 19.42 ± 2.63 nM 与 235.0 ± 165.0 nM，p = 0.0035 对于奈拉替尼）。与单独使用奥拉帕利或奈拉替尼相比，奥拉帕利与奈拉替尼联合使用在体外和体内均更有效，并在所有主要的 HER2 + OC 模型中显示出协同作用。Western blot 实验表明，奈拉替尼降低了 pHER2/neu，同时增加了聚（ADP-核糖）（PAR）酶活性；奥拉帕利增加了 pHER2/Neu 的表达并阻断了 PAR 激活。奥拉帕利/奈拉替尼联合使用可降低 pHER2/Neu 和 PAR 激活。
奥拉帕利和奈拉替尼的联合使用具有协同作用，并对 HER2 + 卵巢癌具有显著的临床前活性。对于对化疗耐药的 HER2+、同源重组修复功能正常的卵巢癌患者，这种联合治疗可能代表一种新的治疗选择。
