Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts
Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts
复制标题
DOI：
10.1038/s41416-021-01609-1
复制
发表时间：
2021-11-03
影响因子：
8.8
通讯作者：
Damia, G.
中科院分区：
文献类型：
--
作者：
Guffanti, F.;Alvisi, M. F.;Damia, G.
背景技术背景：寻找生物标志物来评估卵巢癌（OC）同源重组（HR）功能并预测对治疗的反应是改善可从铂和奥拉帕尼获益的患者选择的迫切临床需求。（聚ADP核糖聚合酶抑制剂，PARPi）为基础的疗法。我们使用了大量OC患者来源的异种移植物（PDX）（n = 47），并根据BRCA 1/2突变、BRCA 1启动子甲基化和HRDetect评分评估了其HR状态。通过免疫荧光对福尔马林固定、石蜡包埋的未处理肿瘤标本中的RAD 51病灶进行定量，并通过实时PCR对21个DNA修复基因的信使RNA表达进行定量。结果：肿瘤HR缺乏可预测铂类和奥拉帕尼的反应。在双子蛋白阳性/复制细胞中评价的RAD 51病灶的基础水平与奥拉帕尼反应强烈负相关。（p = 0.011）;特别是，病灶评分越低，对奥拉帕尼的敏感性越高，而低RAD 51病灶评分似乎与铂活性相关。基础RAD 51病灶评分是OC患者中奥拉帕尼反应的候选预测生物标志物，因为它可以在临床环境中容易地翻译。此外，这些发现证实了OC-PDX作为识别和验证治疗反应生物标志物的可靠工具的重要性。
BACKGROUND: The search for biomarkers to evaluate ovarian cancer (OC) homologous recombination (HR) function and predict the response to therapy is an urgent clinical need to improve the selection of patients who could benefit from platinum- and olaparib (poly-ADP ribose polymerase inhibitors, PARPi)-based therapies.METHODS: We used a large collection of OC patient-derived xenografts (PDXs) (n = 47) and evaluated their HR status based on BRCA1/2 mutations, BRCA1 promoter methylation and the HRDetect score. RAD51 foci were quantified in formalin-fixed, paraffin-embedded untreated tumour specimens by immunofluorescence and the messenger RNA expression of 21 DNA repair genes by real-time PCR.RESULTS: Tumour HR deficiency predicted both platinum and olaparib responses. The basal level of RAD51 foci evaluated in geminin-positive/replicating cells strongly inversely correlated with olaparib response (p = 0.011); in particular, the lower the foci score, the greater the sensitivity to olaparib, while low RAD51 foci score seems to associate with platinum activity.CONCLUSIONS: The basal RAD51 foci score is a candidate predictive biomarker of olaparib response in OC patients as it can be easily translatable in a clinical setting. Moreover, the findings corroborate the importance of OC-PDXs as a reliable tool to identify and validate biomarkers of response to therapy.