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  ORCID: https://orcid.org/0000-0002-4281-426X and Smalley, Matthew J. ORCID: https://orcid.org/0000-0001-9540-1146
2019.
Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours.
Oncotarget
10
(27)
, pp. 2586-2606.
10.18632/oncotarget.26830
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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 |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Biosciences Research Institutes & Centres > 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: | 22 Sep 2024 15:40 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/121103 |
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