Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells.
Inhibition of poly(ADP-ribose) polymerase induces synthetic lethality in BRIP1 deficient ovarian epithelial cells.
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抑制聚（ADP-核糖）聚合酶可诱导BRIP1缺乏卵巢上皮细胞的合成致死性。
DOI：
10.1016/j.ygyno.2020.09.040
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发表时间：
2020-12
影响因子：
4.7
通讯作者：
McDonnell, Kevin J.
中科院分区：
文献类型：
--
作者：
Ciccone, Marcia A.;Adams, Crystal L.;Bowen, Charles;Thakur, Teena;Ricker, Charite;Culver, Julie O.;Maoz, Asaf;Melas, Marilena;Idos, Gregory E.;Jeyasekharan, Anand D.;Matsuo, Koji;Roman, Lynda D.;Gruber, Stephen B.;McDonnell, Kevin J.
同源重组(HR)基因BRCA1相互作用蛋白C末端解旋酶1(BRIP1)的致病变异增加了卵巢癌的风险。PARP抑制剂(PARPI)在BRCA突变的卵巢癌中发挥综合致死作用。有效的人力资源需要BRCA1和BRIP1之间的合作；因此，BRIP1不能预测合成致死性的易感性。在这里，我们研究了BRIP1功能缺陷的卵巢上皮细胞对PARPI的反应，并将这些细胞与那些缺乏BRCA1活性的细胞进行了比较。我们对中国仓鼠卵巢(CHO)上皮细胞进行改造，使其表达BRIP1或BRCA1缺陷基因，并将其与卡铂或顺铂联合或单独应用。我们评估了细胞的增殖和存活；我们计算了抑制浓度以及联合和减少药物指数。BRIP1和BRCA1失活阻碍HR活性，降低细胞增殖，影响DNA损伤修复。接触铂剂会损害细胞的存活。单独接触奥拉帕利会降低BRCA1缺陷细胞的细胞活力，尽管对BRIP1缺陷细胞没有影响。卡铂或顺铂与奥拉帕利联合使用可协同降低细胞存活率，这与合成致死性一致。BRIP1缺陷的卵巢上皮细胞表现出HR缺陷，当暴露于铂制剂/PARPI组合时，导致合成死亡。PARPI本身没有作用；这种缺乏作用可能是由于区分BRIP1的分子性质和/或基因组背景的结果。我们的研究确定BRIP1基因突变是卵巢癌精确药物治疗的靶点。根据基因图谱和基因组背景，这项研究支持将铂制剂/PARPI联合用于卵巢癌的考虑。
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.
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通过使用BRCA1和BRCA2同源模型的ABT-888（PARP抑制剂）和卡铂的组合增强合成致死性。
影响因子：
5.7
作者：
Clark CC;Weitzel JN;O'Connor TR
通讯作者：
O'Connor TR
DOI：
10.1158/1078-0432.ccr-16-3215
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
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作者：
Jiao S;Xia W;Yamaguchi H;Wei Y;Chen MK;Hsu JM;Hsu JL;Yu WH;Du Y;Lee HH;Li CW;Chou CK;Lim SO;Chang SS;Litton J;Arun B;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
10.3
作者：
Ramus, Susan J.;Song, Honglin;Gayther, Simon A.
通讯作者：
Gayther, Simon A.
影响因子：
28.2
作者：
Juvekar A;Burga LN;Hu H;Lunsford EP;Ibrahim YH;Balmañà J;Rajendran A;Papa A;Spencer K;Lyssiotis CA;Nardella C;Pandolfi PP;Baselga J;Scully R;Asara JM;Cantley LC;Wulf GM
通讯作者：
Wulf GM
影响因子：
30.8
作者：
Rafnar, Thorunn;Gudbjartsson, Daniel F.;Stefansson, Kari
通讯作者：
Stefansson, Kari