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.; Smalley, Matthew J.

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 epithelialmesenchymal 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.

• Journal Article Type: Article
• Acceptance Date: Apr 5, 2019
• Online Publication Date: Apr 5, 2019
• Publication Date: Apr 5, 2019
• Deposit Date: Oct 30, 2023
• Publicly Available Date: Oct 31, 2023
• Journal: Oncotarget
• Print ISSN: 1949-2553
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 27
• Pages: 2586-2606
• DOI: https://doi.org/10.18632/oncotarget.26830
• Public URL: https://uwe-repository.worktribe.com/output/11402349