Ordonez, Liliana D, Hay, Trevor, McEwen, Robert, Polanska, Urszula M, Hughes, Adina, Delpuech, Oona, Cadogan, Elaine, Powell, Steve, Dry, Jonathan, Tornillo, Giusy, Silcock, Lucy, Leo, Elisabetta, O'Connor, Mark J, Clarke, Alan R ![]() ![]() |
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Abstract
Tumours defective in the DNA homologous recombination repair pathway can be effectively treated with poly (ADP-ribose) polymerase (PARP) inhibitors; these have proven effective in clinical trials in patients with BRCA gene function-defective cancers. However, resistance observed in both pre-clinical and clinical studies is likely to impact on this treatment strategy. Over-expression of phosphoglycoprotein (P-gp) has been previously suggested as a mechanism of resistance to the PARP inhibitor olaparib in mouse models of Brca1/2-mutant breast cancer. Here, we report that in a Brca2 model treated with olaparib, P-gp upregulation is observed but is not sufficient to confer resistance. Furthermore, resistant/relapsed tumours do not show substantial changes in PK/PD of olaparib, do not downregulate PARP1 or re-establish double stranded DNA break repair by homologous recombination, all previously suggested as mechanisms of resistance. However, resistance is strongly associated with epithelial-mesenchymal transition (EMT) and treatment-naïve tumours given a single dose of olaparib upregulate EMT markers within one hour. Therefore, in this model, olaparib resistance is likely a product of an as-yet unidentified mechanism associated with rapid transition to the mesenchymal phenotype.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Biosciences European Cancer Stem Cell Research Institute (ECSCRI) |
Publisher: | Impact Journals |
ISSN: | 1949-2553 |
Funders: | Cancer Research UK |
Date of First Compliant Deposit: | 25 March 2019 |
Date of Acceptance: | 23 March 2019 |
Last Modified: | 15 Aug 2023 17:44 |
URI: | https://orca.cardiff.ac.uk/id/eprint/121103 |
Citation Data
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