Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells
Objective: Despite the promise of PARP inhibitors (PARPi) for treating <i>BRCA1/2</i> 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 ov...
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MDPI AG
2020-02-01
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| Series: | Diagnostics |
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| Online Access: | https://www.mdpi.com/2075-4418/10/2/121 |
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| author | Brian T. Burgess Abigail M. Anderson J. Robert McCorkle Jianrong Wu Frederick R. Ueland Jill M. Kolesar |
| author_facet | Brian T. Burgess Abigail M. Anderson J. Robert McCorkle Jianrong Wu Frederick R. Ueland Jill M. Kolesar |
| author_sort | Brian T. Burgess |
| collection | DOAJ |
| description | Objective: Despite the promise of PARP inhibitors (PARPi) for treating <i>BRCA1/2</i> 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) <i>gBRCA1</i> 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: IC<sub>50</sub> for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (<i>p</i> = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (<i>p</i> = 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 <i>BRCA1</i> mutated OC cell models, and are rationale combinations for further clinical development. |
| first_indexed | 2024-12-10T07:16:42Z |
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| id | doaj.art-719bebe97d414206880c0a4241d77a68 |
| institution | Directory Open Access Journal |
| issn | 2075-4418 |
| language | English |
| last_indexed | 2024-12-10T07:16:42Z |
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| series | Diagnostics |
| spelling | doaj.art-719bebe97d414206880c0a4241d77a682022-12-22T01:57:55ZengMDPI AGDiagnostics2075-44182020-02-0110212110.3390/diagnostics10020121diagnostics10020121Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian CellsBrian T. Burgess0Abigail M. Anderson1J. Robert McCorkle2Jianrong Wu3Frederick R. Ueland4Jill M. Kolesar5Division of Gynecologic Oncology, Department of OB/GYN, University of Kentucky, Whitney-Hendrickson Building, 800 Rose Street, Lexington, KY 40536, USAMarkey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USAMarkey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USABiostatistics and Bioinformatics Shared Resource Facility, University of Kentucky, 800 Rose Street, Roach Building CC433, Lexington, KY 40536, USADivision of Gynecologic Oncology, Department of OB/GYN, University of Kentucky, Whitney-Hendrickson Building, 800 Rose Street, Lexington, KY 40536, USAMarkey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USAObjective: Despite the promise of PARP inhibitors (PARPi) for treating <i>BRCA1/2</i> 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) <i>gBRCA1</i> 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: IC<sub>50</sub> for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (<i>p</i> = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (<i>p</i> = 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 <i>BRCA1</i> mutated OC cell models, and are rationale combinations for further clinical development.https://www.mdpi.com/2075-4418/10/2/121olaparibparpatrchk1resistancebrca1ovarian cancerinhibitoruwb1.289uwb1.289 + brca |
| spellingShingle | Brian T. Burgess Abigail M. Anderson J. Robert McCorkle Jianrong Wu Frederick R. Ueland Jill M. Kolesar Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells Diagnostics olaparib parp atr chk1 resistance brca1 ovarian cancer inhibitor uwb1.289 uwb1.289 + brca |
| title | Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells |
| title_full | Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells |
| title_fullStr | Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells |
| title_full_unstemmed | Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells |
| title_short | Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant <i>BRCA1</i> Mutant Ovarian Cells |
| title_sort | olaparib combined with an atr or chk1 inhibitor as a treatment strategy for acquired olaparib resistant i brca1 i mutant ovarian cells |
| topic | olaparib parp atr chk1 resistance brca1 ovarian cancer inhibitor uwb1.289 uwb1.289 + brca |
| url | https://www.mdpi.com/2075-4418/10/2/121 |
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