Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer

Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PAR...

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Autores principales: Teo, Zhi Ling, O’Connor, Mark J., Versaci, Stephanie, Clarke, Kylie A., Brown, Emmaline R., Percy, Luke W., Kuykhoven, Keilly, Mintoff, Christopher P., Savas, Peter, Virassamy, Balaji, Luen, Stephen J., Byrne, Ann, Sant, Sneha, Lindeman, Geoffrey J., Darcy, Phillip K., Loi, Sherene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427618/
https://www.ncbi.nlm.nih.gov/pubmed/37582853
http://dx.doi.org/10.1038/s41523-023-00568-5
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author Teo, Zhi Ling
O’Connor, Mark J.
Versaci, Stephanie
Clarke, Kylie A.
Brown, Emmaline R.
Percy, Luke W.
Kuykhoven, Keilly
Mintoff, Christopher P.
Savas, Peter
Virassamy, Balaji
Luen, Stephen J.
Byrne, Ann
Sant, Sneha
Lindeman, Geoffrey J.
Darcy, Phillip K.
Loi, Sherene
author_facet Teo, Zhi Ling
O’Connor, Mark J.
Versaci, Stephanie
Clarke, Kylie A.
Brown, Emmaline R.
Percy, Luke W.
Kuykhoven, Keilly
Mintoff, Christopher P.
Savas, Peter
Virassamy, Balaji
Luen, Stephen J.
Byrne, Ann
Sant, Sneha
Lindeman, Geoffrey J.
Darcy, Phillip K.
Loi, Sherene
author_sort Teo, Zhi Ling
collection PubMed
description Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC.
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spelling pubmed-104276182023-08-17 Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer Teo, Zhi Ling O’Connor, Mark J. Versaci, Stephanie Clarke, Kylie A. Brown, Emmaline R. Percy, Luke W. Kuykhoven, Keilly Mintoff, Christopher P. Savas, Peter Virassamy, Balaji Luen, Stephen J. Byrne, Ann Sant, Sneha Lindeman, Geoffrey J. Darcy, Phillip K. Loi, Sherene NPJ Breast Cancer Article Novel therapeutic strategies that can effectively combine with immunotherapies are needed in the treatment of triple-negative breast cancer (TNBC). We demonstrate that combined PARP and WEE1 inhibition are synergistic in controlling tumour growth in BRCA1/2 wild-type TNBC preclinical models. The PARP inhibitor (PARPi) olaparib combined with the WEE1 inhibitor (WEE1i) adavosertib triggered increases in anti-tumour immune responses, including STING pathway activation. Combinations with a STING agonist resulted in further improved durable tumour regression and significant improvements in survival outcomes in murine tumour models of BRCA1/2 wild-type TNBC. In addition, we have identified baseline tumour-infiltrating lymphocyte (TIL) levels as a potential predictive biomarker of response to PARPi, WEE1i and immunotherapies in BRCA1/2 wild-type TNBC. Nature Publishing Group UK 2023-08-15 /pmc/articles/PMC10427618/ /pubmed/37582853 http://dx.doi.org/10.1038/s41523-023-00568-5 Text en © Crown 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Teo, Zhi Ling
O’Connor, Mark J.
Versaci, Stephanie
Clarke, Kylie A.
Brown, Emmaline R.
Percy, Luke W.
Kuykhoven, Keilly
Mintoff, Christopher P.
Savas, Peter
Virassamy, Balaji
Luen, Stephen J.
Byrne, Ann
Sant, Sneha
Lindeman, Geoffrey J.
Darcy, Phillip K.
Loi, Sherene
Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title_full Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title_fullStr Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title_full_unstemmed Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title_short Combined PARP and WEE1 inhibition triggers anti-tumor immune response in BRCA1/2 wildtype triple-negative breast cancer
title_sort combined parp and wee1 inhibition triggers anti-tumor immune response in brca1/2 wildtype triple-negative breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10427618/
https://www.ncbi.nlm.nih.gov/pubmed/37582853
http://dx.doi.org/10.1038/s41523-023-00568-5
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