Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells
Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells
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DOI：
10.3390/diagnostics10020121
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发表时间：
2020-02-01
期刊：
影响因子：
3.6
通讯作者：
Kolesar, Jill M.
中科院分区：
文献类型：
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作者：
Burgess, Brian T.;Anderson, Abigail M.;Kolesar, Jill M.
目的：尽管PARP抑制剂（PARPi）有望治疗BRCA 1/2突变的卵巢癌（OC），但耐药性总是会发展。我们假设，针对DNA修复途径和细胞周期中的关键分子的合理药物组合可能具有协同作用并克服获得性PARPi耐药性。研究方法：使用细胞增殖试验，在PARPi敏感（UWB 1）和耐药（UWB 1-R）gBRCA 1突变OC细胞系中评估了PARPi单独和与关键DNA修复和细胞周期蛋白抑制剂（包括ATR（VE-821）、Chk 1（MK-8776）、Wee 1（MK-1775）、RAD 51（RI-1））组合的药物敏感性。使用布利斯协同作用模型来估计PARPi与抑制剂组合的两种药物组合效应和药理学协同作用（布利斯评分>= 0）或拮抗作用（布利斯评分>= 0）响应。结果：单独奥拉帕尼的IC 50为1.6 +/- 0.9 μ M，而UWB 1和UWB 1-R细胞的IC 50分别为3.4 +/- 0.6 μ M（p = 0.05）。与UWB 1相比，UWB 1-R对ATRi的敏感性增加（p = 0.04）。奥拉帕尼（0.3-1.25 μ M）和ATRi（0.8-2.5 μ M）对UWB 1和UWB 1-R细胞具有协同作用，布利斯评分分别为17.2 +/-0.2，11.9 +/-0.6。奥拉帕尼（0.3-1.25 μ M）和Chk 1 i（0.05-1.25 μ M）具有协同作用，UWB 1和UWB 1-R细胞的布利斯评分分别为8.3 +/- 1.6、5.7 +/- 2.9。结论：ATRi或Chk 1 i与奥拉帕尼的组合在PARPi敏感和耐药BRCA 1突变OC细胞模型中具有协同作用，并且是进一步临床开发的合理组合。
Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score >= 0) or antagonistic (Bliss score >= 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 +/- 0.9 mu M compared to 3.4 +/- 0.6 mu M (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3-1.25 mu M) and ATRi (0.8-2.5 mu M) were synergistic with Bliss scores of 17.2 +/- 0.2, 11.9 +/- 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3-1.25 mu M) and Chk1i(0.05-1.25 mu M) were synergistic with Bliss scores of 8.3 +/- 1.6, 5.7 +/- 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.