Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells
by
Brian T. Burgess 1
, Abigail M. Anderson 2, J. Robert McCorkle 2, Jianrong Wu 3, Frederick R. Ueland 1 and Jill M. Kolesar 2,4,*
Brian T. Burgess 1, Abigail M. Anderson 2, J. Robert McCorkle 2, Jianrong Wu 3, Frederick R. Ueland 1 and Jill M. Kolesar 2,4,*
1
Division of Gynecologic Oncology, Department of OB/GYN, University of Kentucky, Whitney-Hendrickson Building, 800 Rose Street, Lexington, KY 40536, USA
2
Markey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USA
3
Biostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, 800 Rose Street, Roach Building CC433, Lexington, KY 40536, USA
4
College of Pharmacy, University of Kentucky, 567 Todd Building, 789 South Limestone Street, Lexington, KY 40536, USA
*
Author to whom correspondence should be addressed.
Diagnostics 2020, 10(2), 121; https://doi.org/10.3390/diagnostics10020121
Received: 29 December 2019 / Revised: 11 February 2020 / Accepted: 18 February 2020 / Published: 22 February 2020
(This article belongs to the Special Issue Ovarian Cancer: Characteristics, Screening, Diagnosis and Treatment)
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 µM compared to 3.4 ± 0.6 µM (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 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. 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.
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Keywords:
Olaparib; PARP; ATR; Chk1; resistance; BRCA1; ovarian cancer; inhibitor; UWB1.289; UWB1.289 + BRCA
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MDPI and ACS Style
Burgess, B.T.; Anderson, A.M.; McCorkle, J.R.; Wu, J.; Ueland, F.R.; Kolesar, J.M. Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells. Diagnostics 2020, 10, 121.
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