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Resistance to therapy caused by intragenic deletion in BRCA2

机译：对BRCA2基因内缺失引起的治疗耐药

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Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We derived PARP-inhibitor-resistant (PIR) clones from the human CAPAN1 pancreatic cancer cell line, which carries the protein-truncating c.6174delT frameshift mutation. PIR clones could form DNA-damage-induced RAD51 nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent HR pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the c.6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and HR deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin-resistant ovarian tumours from c.6174delT mutation carriers. These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2.
机译：具有BRCA2功能丧失的细胞在同源重组（HR）中存在缺陷，并且对聚（ADP-核糖）聚合酶（PARP）抑制剂高度敏感，这为新的治疗方法提供了基础。在这里，我们表明对BRAP抑制的抗性可以通过删除BRCA2中的突变来获得。我们从人CAPAN1胰腺癌细胞系衍生了PARP抑制剂抗性（PIR）克隆，该克隆携带蛋白截短的c.6174delT移码突变。 PIR克隆可形成DNA损伤诱导的RAD51核灶，并能够限制基因毒素诱导的基因组不稳定性，这都是有效的HR途径的标志。由于c.6174delT突变的基因内缺失和开放阅读框（ORF）的恢复，新的BRCA2亚型在抗性系中表达。用这些回复性BRCA2等位基因重建BRCA2缺陷细胞可拯救PARP抑制剂敏感性和HR缺陷。 BRCA2中的大多数缺失与小段同源性有关，可能是由于BRCA2缺乏引起的易错修复。来自c.6174delT突变携带者的抗卡铂卵巢肿瘤中也存在类似的ORF恢复突变。这些观察结果对于理解BRCA突变携带者的耐药性以及定义BRCA2中功能上重要的结构域具有重要意义。

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