Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor
Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor
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DOI：
10.1002/path.4140
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发表时间：
2013-02-01
影响因子：
7.3
通讯作者：
Ashworth, Alan
中科院分区：
文献类型：
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作者：
Barber, Louise J.;Sandhu, Shahneen;Ashworth, Alan
用于治疗BRCA1或BRCA2缺陷肿瘤的PARP抑制剂（PARPi）目前是探索合成致死性概念的开创性临床试验的重点。尽管对PARPi的临床耐药已被描述，但其潜在的机制尚未阐明。在这里，我们研究了对PARPi奥拉帕尼产生耐药性的患者的肿瘤物质，随后显示出初步的临床反应。奥拉帕尼治疗初期和治疗后活检的大量平行DNA测序鉴定了肿瘤特异性BRCA2继发性突变在奥拉帕尼耐药转移中。这些继发性突变恢复了全长BRCA2蛋白，并且很可能通过在肿瘤细胞中重建BRCA2功能而引起奥拉帕尼耐药性。版权所有2012年英国和爱尔兰病理学会。约翰·威利父子有限公司出版。
PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells. Copyright (C) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.