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Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells

The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BR...

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Autores principales: Lloyd, Rebecca L., Wijnhoven, Paul W. G., Ramos-Montoya, Antonio, Wilson, Zena, Illuzzi, Giuditta, Falenta, Katarzyna, Jones, Gemma N., James, Neil, Chabbert, Christophe D., Stott, Jonathan, Dean, Emma, Lau, Alan, Young, Lucy A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299845/
https://www.ncbi.nlm.nih.gov/pubmed/32444694
http://dx.doi.org/10.1038/s41388-020-1328-y
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author Lloyd, Rebecca L.
Wijnhoven, Paul W. G.
Ramos-Montoya, Antonio
Wilson, Zena
Illuzzi, Giuditta
Falenta, Katarzyna
Jones, Gemma N.
James, Neil
Chabbert, Christophe D.
Stott, Jonathan
Dean, Emma
Lau, Alan
Young, Lucy A.
author_facet Lloyd, Rebecca L.
Wijnhoven, Paul W. G.
Ramos-Montoya, Antonio
Wilson, Zena
Illuzzi, Giuditta
Falenta, Katarzyna
Jones, Gemma N.
James, Neil
Chabbert, Christophe D.
Stott, Jonathan
Dean, Emma
Lau, Alan
Young, Lucy A.
author_sort Lloyd, Rebecca L.
collection PubMed
description The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1–2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib.
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spelling pubmed-72998452020-06-24 Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells Lloyd, Rebecca L. Wijnhoven, Paul W. G. Ramos-Montoya, Antonio Wilson, Zena Illuzzi, Giuditta Falenta, Katarzyna Jones, Gemma N. James, Neil Chabbert, Christophe D. Stott, Jonathan Dean, Emma Lau, Alan Young, Lucy A. Oncogene Article The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is FDA approved for the treatment of BRCA-mutated breast, ovarian and pancreatic cancers. Olaparib inhibits PARP1/2 enzymatic activity and traps PARP1 on DNA at single-strand breaks, leading to replication-induced DNA damage that requires BRCA1/2-dependent homologous recombination repair. Moreover, DNA damage response pathways mediated by the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia mutated and Rad3-related (ATR) kinases are hypothesised to be important survival pathways in response to PARP-inhibitor treatment. Here, we show that olaparib combines synergistically with the ATR-inhibitor AZD6738 (ceralasertib), in vitro, leading to selective cell death in ATM-deficient cells. We observe that 24 h olaparib treatment causes cells to accumulate in G2-M of the cell cycle, however, co-administration with AZD6738 releases the olaparib-treated cells from G2 arrest. Selectively in ATM-knockout cells, we show that combined olaparib/AZD6738 treatment induces more chromosomal aberrations and achieves this at lower concentrations and earlier treatment time-points than either monotherapy. Furthermore, single-agent olaparib efficacy in vitro requires PARP inhibition throughout multiple rounds of replication. Here, we demonstrate in several ATM-deficient cell lines that the olaparib and AZD6738 combination induces cell death within 1–2 cell divisions, suggesting that combined treatment could circumvent the need for prolonged drug exposure. Finally, we demonstrate in vivo combination activity of olaparib and AZD6738 in xenograft and PDX mouse models with complete ATM loss. Collectively, these data provide a mechanistic understanding of combined PARP and ATR inhibition in ATM-deficient models, and support the clinical development of AZD6738 in combination with olaparib. Nature Publishing Group UK 2020-05-23 2020 /pmc/articles/PMC7299845/ /pubmed/32444694 http://dx.doi.org/10.1038/s41388-020-1328-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Lloyd, Rebecca L.
Wijnhoven, Paul W. G.
Ramos-Montoya, Antonio
Wilson, Zena
Illuzzi, Giuditta
Falenta, Katarzyna
Jones, Gemma N.
James, Neil
Chabbert, Christophe D.
Stott, Jonathan
Dean, Emma
Lau, Alan
Young, Lucy A.
Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title_full Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title_fullStr Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title_full_unstemmed Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title_short Combined PARP and ATR inhibition potentiates genome instability and cell death in ATM-deficient cancer cells
title_sort combined parp and atr inhibition potentiates genome instability and cell death in atm-deficient cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299845/
https://www.ncbi.nlm.nih.gov/pubmed/32444694
http://dx.doi.org/10.1038/s41388-020-1328-y
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