• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers
【24h】

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers

机译：继发突变是BRCA2突变癌症中顺铂耐药的机制。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown. Here we show that acquired resistance to cisplatin can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. First, in a cisplatin-resistant BRCA2-mutated breast-cancer cell line, HCC1428, a secondary genetic change in BRCA2 rescued BRCA2 function. Second, cisplatin selection of a BRCA2-mutated pancreatic cancer cell line, Capan-1 (refs 3, 4), led to five different secondary mutations that restored the wild-type BRCA2 reading frame. All clones with secondary mutations were resistant both to cisplatin and to a poly(ADP-ribose) polymerase (PARP) inhibitor (AG14361). Finally, we evaluated recurrent cancers from patients whose primary BRCA2-mutated ovarian carcinomas were treated with cisplatin. The recurrent tumour that acquired cisplatin resistance had undergone reversion of its BRCA2 mutation. Our results suggest that secondary mutations that restore the wild-type BRCA2 reading frame may be a major clinical mediator of acquired resistance to platinum-based chemotherapy.
机译：在肿瘤抑制因子BRCA2中发生突变的卵巢癌对铂化合物特别敏感。但是，此类癌症最终会产生顺铂耐药性。这种抵抗的机制在很大程度上尚不清楚。在这里，我们显示获得的对顺铂的耐药性可以通过恢复野生型BRCA2阅读框的BRCA2的第二代基因内突变来介导。首先，在顺铂耐药的BRCA2突变乳腺癌细胞系HCC1428中，BRCA2的继发性遗传改变挽救了BRCA2的功能。其次，对BRCA2突变的胰腺癌细胞系Capan-1的顺铂选择（参考文献3、4）导致了五个不同的次级突变，它们恢复了野生型BRCA2阅读框。所有具有次级突变的克隆均对顺铂和聚（ADP-核糖）聚合酶（PARP）抑制剂（AG14361）均具有抗性。最后，我们评估了用顺铂治疗原发性BRCA2突变的卵巢癌患者的复发性癌症。获得顺铂耐药性的复发性肿瘤已经恢复了其BRCA2突变。我们的研究结果表明，恢复野生型BRCA2阅读框的二级突变可能是获得的对铂类化学疗法耐药的主要临床介质。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号