Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids.
Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids.
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DOI：
10.1158/2159-8290.cd-18-0474
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发表时间：
2018-11
期刊：
影响因子：
28.2
通讯作者：
D'Andrea AD
中科院分区：
文献类型：
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作者：
Hill SJ;Decker B;Roberts EA;Horowitz NS;Muto MG;Worley MJ Jr;Feltmate CM;Nucci MR;Swisher EM;Nguyen H;Yang C;Morizane R;Kochupurakkal BS;Do KT;Konstantinopoulos PA;Liu JF;Bonventre JV;Matulonis UA;Shapiro GI;Berkowitz RS;Crum CP;D'Andrea AD
根据基因组分析，预计50%的高级别浆液性卵巢癌（HGSC）存在DNA修复缺陷。HGSC的这一重要子集是否真的具有功能性修复缺陷仍然未知。在这里，我们设计了一个在短期患者来源的HGSC类器官中功能性分析DNA修复的平台。我们测试了来自22名HGSC患者的33种类器官培养物的同源重组（HR）和复制叉保护缺陷。无论DNA修复基因突变状态如何，类器官中HR的功能缺陷与PARP抑制剂敏感性相关。复制叉保护的功能缺陷与卡铂和CHK1和ATR抑制剂敏感性相关。我们的研究结果表明，基因组分析和类器官功能测试的组合允许识别靶向DNA损伤修复缺陷。必须分析大量患者来源的类器官，以确定这些测定是否可以在临床上重复预测患者的反应。
Based on genomic analysis, fifty percent of high grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functionally profiling DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 HGSC patients for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.