Department of Gynecology and Obstetrics, Shanghai Key Laboratory of Gynecology Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Research Center for Marine Drugs, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Pharmacol Res. 2022 May;179:106232. doi: 10.1016/j.phrs.2022.106232. Epub 2022 Apr 21.
With the common use of poly ADP-ribose polymerase inhibitors (PARPi) for the man-agement of epithelial ovarian cancer (EOC) across the treatment life cycle, there is a critical need for the development of functional tests, as a complementary to genomic assays, in the study of PARPi sensitivity and resistance. Patient-derived organoids (PDOs) are found feasible for rapid functional testing and predicting drug response. Here, we established a series of PDOs from EOC and tested the sensitivity of seven cases to various agents including PARPi. PDOs recapitulated patient clinical response to platinum chemotherapy and displayed drug response heterogeneity to targeted agents including PARPi. Of three PDOs harboring mutational signature of homologous recombination repair (HRR) deficiency, two were PARPi sensitive while one was inherent resistant. Another PDO derived from a patient who relapsed during olaparib maintenance therapy was found acquired resistant to PARPi. Subsequent functional analysis revealed the potential resistant mechanisms related to replication fork protection and HRR functional restoration, and combination strategies targeting the mechanisms could reverse the resistance. Our research demonstrated the capacity of EOC PDOs for evaluating the sensitivity to PARPi under different settings, exploring mechanisms of resistance, and identifying effective combined strategies, which has implications for the clinical application of PARPi.
随着聚 ADP-核糖聚合酶抑制剂（PARPi）在治疗卵巢上皮癌（EOC）的整个治疗周期中的普遍应用，迫切需要开发功能测试，作为基因组检测的补充，以研究 PARPi 的敏感性和耐药性。患者来源的类器官（PDO）被认为可用于快速功能测试和预测药物反应。在这里，我们从 EOC 中建立了一系列 PDO，并测试了七种情况对包括 PARPi 在内的各种药物的敏感性。PDO 重现了患者对铂类化疗的临床反应，并显示出对靶向药物（包括 PARPi）的药物反应异质性。在三个携带同源重组修复（HRR）缺陷突变特征的 PDO 中，有两个对 PARPi 敏感，而一个是固有耐药的。另一个从奥拉帕利维持治疗期间复发的患者中衍生的 PDO 被发现对 PARPi 获得性耐药。随后的功能分析揭示了与复制叉保护和 HRR 功能恢复相关的潜在耐药机制，针对这些机制的联合策略可以逆转耐药性。我们的研究表明，EOC PDO 有能力在不同环境下评估对 PARPi 的敏感性，探索耐药机制，并确定有效的联合策略，这对 PARPi 的临床应用具有重要意义。
