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Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours

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 and Smalley, Matthew J. 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: Biosciences
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: 30 Sep 2019 20:44
URI: http://orca.cf.ac.uk/id/eprint/121103

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