Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.
Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.
复制标题
DOI：
10.18632/oncotarget.10308
复制
发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Mes-Masson AM
中科院分区：
文献类型：
--
作者：
Fleury H;Carmona E;Morin VG;Meunier L;Masson JY;Tonin PN;Provencher D;Mes-Masson AM
PARP抑制剂（PARPi），如奥拉帕尼，在高级别浆液性（HGS）上皮性卵巢癌（EOC）治疗中显示出有希望的结果。PARPi敏感性主要与同源重组（HR）缺陷有关，但临床试验表明，预测患者的实际反应是复杂的。在这里，我们研究了18种不同的HGS EOC细胞系的基因表达芯片、HR功能和奥拉帕尼敏感性，并证明PARPi敏感性不仅与HR缺陷有关。基因靶标验证表明，下调核苷酸切除修复（NER）和错配修复（MMR）途径（分别为ERCC8和MLH1）中的基因会增加PARPi的应答。当HR和NER或MMR通路中的基因同时下调时，观察到最高的敏感性。通过临床样本，可以识别出这些同时下调的患者。在此基础上，提出了一种新的预测PARPi灵敏度的模型。该模型表明，在临床试验中确定的极端应答者在HR和NER或MMR方面存在缺陷。
PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.