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Lookup NU author(s): Dr Asima Mukhopadhyay, Dr Yvette DrewORCiD, Liz Matheson, Dr Mo Salehan, Lucy Gentles, Professor Nicola CurtinORCiD
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© 2018 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.
Author(s): Mukhopadhyay A, Drew Y, Matheson E, Salehan M, Gentles L, Pachter JA, Curtin NJ
Publication type: Article
Publication status: Published
Journal: Biochemical Pharmacology
Year: 2019
Volume: 167
Pages: 125-132
Print publication date: 01/09/2019
Online publication date: 17/10/2018
Acceptance date: 15/10/2018
ISSN (print): 0006-2952
ISSN (electronic): 1873-2968
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.bcp.2018.10.011
DOI: 10.1016/j.bcp.2018.10.011
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