Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.
Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models.
复制标题
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。
DOI：
10.1158/1535-7163.mct-11-0597
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发表时间：
2012-09
影响因子：
5.7
通讯作者：
O'Connor TR
中科院分区：
文献类型：
--
作者：
Clark CC;Weitzel JN;O'Connor TR
具有遗传性BRCA 1或BRCA 2突变的个体患乳腺癌（BC）的风险升高。由此产生的肿瘤通常缺乏同源重组修复，如具有获得性BRCA缺陷的散发性肿瘤的子集。铂类药物或聚（ADP）核糖聚合酶（PARP）抑制剂（PARPi）单药治疗BRCA相关癌症的临床反应已得到证实。然而，关于PARPi和铂类药物的联合治疗、这种联合治疗的作用机制以及BRCA 1或BRCA 2在化学敏感性中的作用的数据有限。我们通过检查处理过的Brca-熟练和缺乏的小鼠胚胎干细胞（mESC）的存活率，比较了ABT-888（PARPi）与顺铂或卡铂（铂类药物）单独或联合治疗的疗效。此外，药物诱导的BRCA 1和BRCA 2无效细胞系的生长抑制进行了比较，其同基因BRCA补充线。尽管每种单一疗法杀死或抑制Brca/BRCA缺陷细胞的增殖，但在用ABT-888与卡铂组合治疗后观察到增强的效果。此外，ABT-888/卡铂组合延迟了Brca 2异种移植物中的肿瘤生长。这些药物导致DNA损伤，细胞凋亡和更大的PARP活性在Brca/BRCA缺陷细胞，这些影响与化疗敏感性增加。我们的数据表明，ABT-888和卡铂联合治疗在解决许多BRCA相关癌症方面比单药治疗更成功。最近启动了一项随机II期试验来验证这一假设，以帮助发现更有效的BRCA患者治疗方法。
Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer (BC). The resulting tumors typically lack homologous recombination repair, as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly(ADP)ribose polymerase (PARP) inhibitors (PARPi) have been demonstrated for BRCA-associated cancers. However, there is limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining survival of treated Brca-proficient and -deficient mouse embryonic stem cells (mESC). In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared to their isogenic BRCA-complemented lines. Whereas each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage, apoptosis and greater PARP activity in Brca/BRCA-deficient cells, and these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for BRCA patients.