The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing...

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Autores principales:	Stijn Moens, Peihua Zhao, Maria Francesca Baietti, Oliviero Marinelli, Delphi Van Haver, Francis Impens, Giuseppe Floris, Elisabetta Marangoni, Patrick Neven, Daniela Annibali, Anna A. Sablina, Frédéric Amant
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/23a5f34fef334ff789f85c69f707a9be
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spelling	oai:doaj.org-article:23a5f34fef334ff789f85c69f707a9be2021-12-02T10:44:15ZThe mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers10.1038/s41598-021-82780-62045-2322https://doaj.org/article/23a5f34fef334ff789f85c69f707a9be2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82780-6https://doaj.org/toc/2045-2322Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.Stijn MoensPeihua ZhaoMaria Francesca BaiettiOliviero MarinelliDelphi Van HaverFrancis ImpensGiuseppe FlorisElisabetta MarangoniPatrick NevenDaniela AnnibaliAnna A. SablinaFrédéric AmantNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stijn Moens Peihua Zhao Maria Francesca Baietti Oliviero Marinelli Delphi Van Haver Francis Impens Giuseppe Floris Elisabetta Marangoni Patrick Neven Daniela Annibali Anna A. Sablina Frédéric Amant The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
description	Abstract Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, lacking effective therapy. Many TNBCs show remarkable response to carboplatin-based chemotherapy, but often develop resistance over time. With increasing use of carboplatin in the clinic, there is a pressing need to identify vulnerabilities of carboplatin-resistant tumors. In this study, we generated carboplatin-resistant TNBC MDA-MB-468 cell line and patient derived TNBC xenograft models. Mass spectrometry-based proteome profiling demonstrated that carboplatin resistance in TNBC is linked to drastic metabolism rewiring and upregulation of anti-oxidative response that supports cell replication by maintaining low levels of DNA damage in the presence of carboplatin. Carboplatin-resistant cells also exhibited dysregulation of the mitotic checkpoint. A kinome shRNA screen revealed that carboplatin-resistant cells are vulnerable to the depletion of the mitotic checkpoint regulators, whereas the checkpoint kinases CHEK1 and WEE1 are indispensable for the survival of carboplatin-resistant cells in the presence of carboplatin. We confirmed that pharmacological inhibition of CHEK1 by prexasertib in the presence of carboplatin is well tolerated by mice and suppresses the growth of carboplatin-resistant TNBC xenografts. Thus, abrogation of the mitotic checkpoint by CHEK1 inhibition re-sensitizes carboplatin-resistant TNBCs to carboplatin and represents a potential strategy for the treatment of carboplatin-resistant TNBCs.
format	article
author	Stijn Moens Peihua Zhao Maria Francesca Baietti Oliviero Marinelli Delphi Van Haver Francis Impens Giuseppe Floris Elisabetta Marangoni Patrick Neven Daniela Annibali Anna A. Sablina Frédéric Amant
author_facet	Stijn Moens Peihua Zhao Maria Francesca Baietti Oliviero Marinelli Delphi Van Haver Francis Impens Giuseppe Floris Elisabetta Marangoni Patrick Neven Daniela Annibali Anna A. Sablina Frédéric Amant
author_sort	Stijn Moens
title	The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
title_short	The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
title_full	The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
title_fullStr	The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
title_full_unstemmed	The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
title_sort	mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/23a5f34fef334ff789f85c69f707a9be
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The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

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