Wilkerson Paul M, Dedes Konstantin J, Samartzis Eleftherios Pierre, Dedes Ioannis, Lambros Maryou B, Natrajan Rachael, Gauthier Arnaud, Piscuoglio Salvatore, Töpfer Chantal, Vukovic Vesna, Daley Frances, Weigelt Britta, Reis-Filho Jorge S
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, SW3 6JB, UK.
Department of Gynaecology, University Hospital of Zurich, 8091 Zurich, Switzerland.
Oncotarget. 2017 Jan 24;8(4):6057-6066. doi: 10.18632/oncotarget.14011.
To determine if models of ovarian clear cell carcinomas (OCCCs) harbouring defects in homologous recombination (HR) DNA repair of double strand breaks (DSBs) are sensitive to cisplatin and/or PARP inhibition.
The HR status of 12 OCCC cell lines was determined using RAD51/γH2AX foci formation assays. Sensitivity to cisplatin and the PARP inhibitor BMN-673 was correlated with HR status. BRCA1, BRCA2, MRE11 and PTEN loss of expression was investigated as a potential determinant of BMN-673 sensitivity. A tissue microarray containing 50 consecutive primary OCCC was assessed for PTEN expression using immunohistochemistry.
A subset of OCCC cells displayed reduced RAD51 foci formation in the presence of DNA DSBs, suggestive of HR defects. HR-defective OCCC cells, with the exception of KOC-7c, had higher sensitivity to cisplatin/ BMN-673 than HR-competent OCCC cell lines (Log10 SF50 -9.4 (SD +/- 0.29) vs -8.1 (SD +/- 0.35), mean difference 1.3, p < 0.01). Of the cell lines studied, two, TOV-21G and KOC-7c, showed loss of PTEN expression. In primary OCCCs, loss of PTEN expression was observed in 10% (5/49) of cases.
A subset of OCCC cells are sensitive to PARP inhibition in vitro, which can be predicted by HR defects as defined by γH2AX/RAD51 foci formation. These results provide a rationale for the testing of HR deficiency and PARP inhibitors as a targeted therapy in a subset of OCCCs.
确定携带双链断裂（DSB）同源重组（HR）DNA修复缺陷的卵巢透明细胞癌（OCCC）模型对顺铂和/或PARP抑制是否敏感。
使用RAD51/γH2AX焦点形成试验确定12种OCCC细胞系的HR状态。对顺铂和PARP抑制剂BMN-673的敏感性与HR状态相关。研究了BRCA1、BRCA2、MRE11和PTEN表达缺失作为BMN-673敏感性的潜在决定因素。使用免疫组织化学评估包含50个连续原发性OCCC的组织微阵列的PTEN表达。
一部分OCCC细胞在存在DNA DSB的情况下显示RAD51焦点形成减少，提示HR缺陷。除KOC-7c外，HR缺陷的OCCC细胞比HR功能正常的OCCC细胞系对顺铂/BMN-673更敏感（Log10 SF50 -9.4（标准差±0.29）对-8.1（标准差±0.35），平均差异1.3，p<0.01）。在所研究的细胞系中，TOV-21G和KOC-7c这两种细胞系显示PTEN表达缺失。在原发性OCCC中，10%（5/49）的病例观察到PTEN表达缺失。
一部分OCCC细胞在体外对PARP抑制敏感，这可以通过γH2AX/RAD51焦点形成所定义的HR缺陷来预测。这些结果为检测HR缺陷和PARP抑制剂作为一部分OCCC的靶向治疗提供了理论依据。
