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

Autor:	Ordonez LD; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK., Hay T; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK., McEwen R; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Polanska UM; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Hughes A; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Delpuech O; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Cadogan E; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Powell S; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Dry J; Oncology, IMED Biotech Unit, AstraZeneca, Waltham, MA, USA., Tornillo G; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK., Silcock L; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK., Leo E; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., O'Connor MJ; Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK., Clarke AR; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.; Posthumous authorship., Smalley MJ; European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2019 Apr 05; Vol. 10 (27), pp. 2586-2606. Date of Electronic Publication: 2019 Apr 05 (Print Publication: 2019).
DOI:	10.18632/oncotarget.26830
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST RM, UP, AH, OD, SP, JD, EC, EL and MO are employees of AstraZeneca.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu