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

2019; Impact Journals LLC; Volume: 10; Issue: 27 Linguagem: Inglês

10.18632/oncotarget.26830

1949-2553

Liliana Ordonez, Trevor Hay, Robert McEwen, Urszula M. Polanska, Adina Hughes, Oona Delpuech, Elaine Cadogan, Steve Powell, Jonathan R. Dry, Giusy Tornillo, Lucy Silcock, Elisabetta Leo, Mark J. O’Connor, Alan R. Clarke, Matthew J. Smalley,

BRCA gene mutations in cancer

// Liliana D. Ordonez 1 , Trevor Hay 1 , Robert McEwen 2 , Urszula M. Polanska 2 , Adina Hughes 2 , Oona Delpuech 2 , Elaine Cadogan 2 , Steve Powell 2 , Jonathan Dry 3 , Giusy Tornillo 1 , Lucy Silcock 1 , Elisabetta Leo 2 , Mark J. O’Connor 2 , Alan R. Clarke 1 , * and Matthew J. Smalley 1 1 European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK 2 Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK 3 Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA * Posthumous authorship Correspondence to: Matthew J. Smalley, email: SmalleyMJ@cf.ac.uk Keywords: PARP inhibitors; olaparib; Brca2; EMT; P-gps Received: November 14, 2018     Accepted: March 23, 2019     Published: April 05, 2019 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.