Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition

Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these mar...

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Autores principales:	Diar Aziz, Neil Portman, Kristine J. Fernandez, Christine Lee, Sarah Alexandrou, Alba Llop-Guevara, Zoe Phan, Aliza Yong, Ashleigh Wilkinson, C. Marcelo Sergio, Danielle Ferraro, Dariush Etemadmoghadam, David D. Bowtell, kConFab Investigators, Violeta Serra, Paul Waring, Elgene Lim, C. Elizabeth Caldon
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6daf1a428240435b83fc21ea45524a31
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spelling	oai:doaj.org-article:6daf1a428240435b83fc21ea45524a312021-12-02T19:10:22ZSynergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition10.1038/s41523-021-00312-x2374-4677https://doaj.org/article/6daf1a428240435b83fc21ea45524a312021-08-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00312-xhttps://doaj.org/toc/2374-4677Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.Diar AzizNeil PortmanKristine J. FernandezChristine LeeSarah AlexandrouAlba Llop-GuevaraZoe PhanAliza YongAshleigh WilkinsonC. Marcelo SergioDanielle FerraroDariush EtemadmoghadamDavid D. BowtellkConFab InvestigatorsVioleta SerraPaul WaringElgene LimC. Elizabeth CaldonNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Diar Aziz Neil Portman Kristine J. Fernandez Christine Lee Sarah Alexandrou Alba Llop-Guevara Zoe Phan Aliza Yong Ashleigh Wilkinson C. Marcelo Sergio Danielle Ferraro Dariush Etemadmoghadam David D. Bowtell kConFab Investigators Violeta Serra Paul Waring Elgene Lim C. Elizabeth Caldon Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
description	Abstract Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
format	article
author	Diar Aziz Neil Portman Kristine J. Fernandez Christine Lee Sarah Alexandrou Alba Llop-Guevara Zoe Phan Aliza Yong Ashleigh Wilkinson C. Marcelo Sergio Danielle Ferraro Dariush Etemadmoghadam David D. Bowtell kConFab Investigators Violeta Serra Paul Waring Elgene Lim C. Elizabeth Caldon
author_facet	Diar Aziz Neil Portman Kristine J. Fernandez Christine Lee Sarah Alexandrou Alba Llop-Guevara Zoe Phan Aliza Yong Ashleigh Wilkinson C. Marcelo Sergio Danielle Ferraro Dariush Etemadmoghadam David D. Bowtell kConFab Investigators Violeta Serra Paul Waring Elgene Lim C. Elizabeth Caldon
author_sort	Diar Aziz
title	Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
title_short	Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
title_full	Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
title_fullStr	Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
title_full_unstemmed	Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition
title_sort	synergistic targeting of brca1 mutated breast cancers with parp and cdk2 inhibition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6daf1a428240435b83fc21ea45524a31
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Synergistic targeting of BRCA1 mutated breast cancers with PARP and CDK2 inhibition

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