USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Gynecol Oncol. 2020 Dec;159(3):869-876. doi: 10.1016/j.ygyno.2020.09.040. Epub 2020 Oct 5.
Pathogenic variations in the homologous recombination (HR) gene, BRCA1 interacting protein C-terminal helicase 1 (BRIP1) increase the risk for ovarian cancer. PARP inhibitors (PARPi) exert a synthetic lethal effect in BRCA-mutated ovarian cancers. Effective HR requires cooperation between BRCA1 and BRIP1; therefore, BRIP1-incompetancy may predict vulnerability to synthetic lethality. Here we investigated the response of ovarian epithelial cells with defective BRIP1 function to PARPi, and compared these cells to those lacking BRCA1 activity.
We engineered Chinese Hamster ovarian (CHO) epithelial cells to express deficient BRIP1 or BRCA1, and exposed them to olaparib with or without carboplatin or cisplatin. We assessed cellular proliferation and survival; we calculated inhibitory concentrations and combination and reduction drug indices.
BRIP1 and BRCA1 inactivation impedes HR activity, decreases cellular proliferation and compromises DNA damage recovery. Platinum agent exposure impairs cellular survival. Olaparib exposure alone decreases cell viability in BRCA1-deficient cells, although has no effect on BRIP1-deficient cells. Combining carboplatin or cisplatin with olaparib synergistically attenuates cellular survival, consistent with synthetic lethality.
BRIP1-deficient ovarian epithelial cells exhibit defective HR, resulting in synthetic lethality when exposed to a platinum agent/PARPi combination. PARPi alone had no effect; this lack of effect may result from distinguishing molecular properties of BRIP1and/or consequences of genomic background. Our study identifies altered BRIP1 as a target for precision medicine-based therapies for ovarian cancers. This investigation supports consideration of the use of a platinum agent/PARPi combination in ovarian cancers depending upon genetic profile and genomic background.
同源重组（HR）基因 BRCA1 相互作用蛋白 C 端解旋酶 1（BRIP1）的致病性变异增加了卵巢癌的风险。聚腺苷二磷酸核糖聚合酶（PARPi）在 BRCA 突变型卵巢癌中发挥合成致死作用。有效的 HR 需要 BRCA1 和 BRIP1 之间的合作；因此，BRIP1 功能不全可能预示着对合成致死的易感性。在这里，我们研究了具有缺陷 BRIP1 功能的卵巢上皮细胞对 PARPi 的反应，并将这些细胞与缺乏 BRCA1 活性的细胞进行了比较。
我们设计了中国仓鼠卵巢（CHO）上皮细胞表达缺陷型 BRIP1 或 BRCA1，并将它们暴露于奥拉帕利加或不加卡铂或顺铂。我们评估了细胞增殖和存活；我们计算了抑制浓度和组合及减少药物指数。
BRIP1 和 BRCA1 的失活会阻碍 HR 活性，降低细胞增殖并损害 DNA 损伤的恢复。铂剂暴露会损害细胞存活。奥拉帕利单独暴露会降低 BRCA1 缺陷细胞的细胞活力，尽管对 BRIP1 缺陷细胞没有影响。铂剂与奥拉帕利联合使用可协同降低细胞存活率，这与合成致死一致。
BRIP1 缺陷型卵巢上皮细胞表现出 HR 缺陷，当暴露于铂剂/PARPi 联合时会导致合成致死。PARPi 单独使用没有效果；这种没有效果的可能是由于 BRIP1 的分子特性和/或基因组背景的后果不同所致。我们的研究确定了改变的 BRIP1 是基于精准医学的卵巢癌治疗的靶点。这项研究支持根据遗传特征和基因组背景考虑使用铂剂/PARPi 联合治疗卵巢癌。
