Burgess Brian T, Anderson Abigail M, McCorkle J Robert, Wu Jianrong, Ueland Frederick R, Kolesar Jill M
Division of Gynecologic Oncology, Department of OB/GYN, University of Kentucky, Whitney-Hendrickson Building, 800 Rose Street, Lexington, KY 40536, USA.
Markey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USA.
Diagnostics (Basel). 2020 Feb 22;10(2):121. doi: 10.3390/diagnostics10020121.
Despite the promise of PARP inhibitors (PARPi) for treating 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.
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) 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.
IC for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM ( = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi ( = 0.04) compared to UWB1. Olaparib (0.3-1.25 µM) and ATRi (0.8-2.5 µM) 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 µM) and Chk1i(0.05-1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively.
Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant mutated OC cell models, and are rationale combinations for further clinical development.
尽管聚（ADP - 核糖）聚合酶抑制剂（PARPi）有望用于治疗突变型卵巢癌（OC），但耐药性仍不可避免地出现。我们推测，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。
使用细胞增殖试验，评估PARPi敏感（UWB1）和耐药（UWB1 - R）的突变型OC细胞系对单独使用PARPi以及与关键DNA修复和细胞周期蛋白抑制剂（包括ATR（VE - 821）、Chk1（MK - 8776）、Wee1（MK - 1775）、RAD51（RI - 1））联合使用时的药物敏感性。采用布利斯协同模型来估计两药联合效应以及PARPi与抑制剂联合时的药理协同（布利斯评分≥0）或拮抗（布利斯评分＜0）反应。
奥拉帕利单独使用时，UWB1细胞和UWB1 - R细胞的半数抑制浓度（IC）分别为1.6±0.9μM和3.4±0.6μM（P = 0.05）。与UWB1相比，UWB1 - R对ATR抑制剂（ATRi）表现出更高的敏感性（P = 0.04）。奥拉帕利（0.3 - 1.25μM）和ATRi（0.8 - 2.5μM）具有协同作用，UWB1细胞和UWB1 - R细胞的布利斯评分分别为17.2±0.2和11.9±0.6。奥拉帕利（0.3 - 1.25μM）和Chk1抑制剂（Chk1i，0.05 - 1.25μM）具有协同作用，UWB1细胞和UWB1 - R细胞的布利斯评分分别为8.3±1.6和5.7±2.9。
在PARPi敏感和耐药的突变型OC细胞模型中，将ATRi或Chk1i与奥拉帕利联合使用具有协同作用，是进一步临床开发的合理组合。
