Evaluating the potential of kinase inhibitors to suppress DNA repair and sensitise ovarian cancer cells to PARP inhibitors
Copyright © 2018. Published by Elsevier Inc..
PARP inhibitors (PARPi) represent a major advance in the treatment of ovarian cancer associated with defects in homologous recombination DNA repair (HRR), primarily due to mutations in BRCA genes. Imatinib and PI3K inhibitors are reported to downregulate HRR and, in some cases, sensitise cells to PARPi. We investigated the ability of imatinib, and the PI3K inhibitors: NVP-BEZ235 and VS-5584, to downregulate HRR and sensitise paired ovarian cancer cells with mutant and reconstituted BRCA1 to the PARPi, olaparib and rucaparib. Olaparib and imatinib combinations were also measured in primary cultures of ovarian cancer. NVP-BEZ235 and imatinib reduced RAD51 levels and focus formation (an indication of HRR function), but VS-5584 did not. In colony-forming assays none of the inhibitors sensitised cells to PARPi cytotoxicity, in fact there was a mild protective effect. These conflicting data were resolved by the observation that the kinase inhibitors reduced the S-phase fraction, when HRR proteins are at their peak and cells are sensitive to PARPi cytotoxicity. In contrast, in primary cultures in 96-well plate assays, imatinib did increase olaparib-induced growth inhibition. However, in one primary culture that could be used in colony-formation cytotoxicity assays, imatinib protected from olaparib cytotoxicity. The kinase inhibitors protect from PARPi cytotoxicity by arresting cell growth, but this may be interpreted as synergy on the basis of 96-well cell growth assays. We urge caution before combining these drugs clinically.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:167 |
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| Enthalten in: |
Biochemical pharmacology - 167(2019) vom: 18. Sept., Seite 125-132 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Mukhopadhyay, Asima [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 30.03.2020 Date Revised 10.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bcp.2018.10.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a PARP inhibitors (PARPi) represent a major advance in the treatment of ovarian cancer associated with defects in homologous recombination DNA repair (HRR), primarily due to mutations in BRCA genes. Imatinib and PI3K inhibitors are reported to downregulate HRR and, in some cases, sensitise cells to PARPi. We investigated the ability of imatinib, and the PI3K inhibitors: NVP-BEZ235 and VS-5584, to downregulate HRR and sensitise paired ovarian cancer cells with mutant and reconstituted BRCA1 to the PARPi, olaparib and rucaparib. Olaparib and imatinib combinations were also measured in primary cultures of ovarian cancer. NVP-BEZ235 and imatinib reduced RAD51 levels and focus formation (an indication of HRR function), but VS-5584 did not. In colony-forming assays none of the inhibitors sensitised cells to PARPi cytotoxicity, in fact there was a mild protective effect. These conflicting data were resolved by the observation that the kinase inhibitors reduced the S-phase fraction, when HRR proteins are at their peak and cells are sensitive to PARPi cytotoxicity. In contrast, in primary cultures in 96-well plate assays, imatinib did increase olaparib-induced growth inhibition. However, in one primary culture that could be used in colony-formation cytotoxicity assays, imatinib protected from olaparib cytotoxicity. The kinase inhibitors protect from PARPi cytotoxicity by arresting cell growth, but this may be interpreted as synergy on the basis of 96-well cell growth assays. We urge caution before combining these drugs clinically | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Homologous recombination | |
| 650 | 4 | |a Imatinib | |
| 650 | 4 | |a Ovarian cancer | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a PI3K mTOR inhibitors | |
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| 700 | 1 | |a Matheson, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Salehan, Mo |e verfasserin |4 aut | |
| 700 | 1 | |a Gentles, Lucy |e verfasserin |4 aut | |
| 700 | 1 | |a Pachter, Jonathan A |e verfasserin |4 aut | |
| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
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