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

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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.
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Multidisciplinary

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Citation

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MLA
Moens, Stijn, et al. “The Mitotic Checkpoint Is a Targetable Vulnerability of Carboplatin-Resistant Triple Negative Breast Cancers.” SCIENTIFIC REPORTS, vol. 11, 2021, doi:10.1038/s41598-021-82780-6.
APA
Moens, S., Zhao, P., Baietti, M. F., Marinelli, O., Van Haver, D., Impens, F., … Amant, F. (2021). The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers. SCIENTIFIC REPORTS, 11. https://doi.org/10.1038/s41598-021-82780-6
Chicago author-date
Moens, Stijn, Peihua Zhao, Maria Francesca Baietti, Oliviero Marinelli, Delphi Van Haver, Francis Impens, Giuseppe Floris, et al. 2021. “The Mitotic Checkpoint Is a Targetable Vulnerability of Carboplatin-Resistant Triple Negative Breast Cancers.” SCIENTIFIC REPORTS 11. https://doi.org/10.1038/s41598-021-82780-6.
Chicago author-date (all authors)
Moens, Stijn, Peihua Zhao, Maria Francesca Baietti, Oliviero Marinelli, Delphi Van Haver, Francis Impens, Giuseppe Floris, Elisabetta Marangoni, Patrick Neven, Daniela Annibali, Anna A. Sablina, and Frédéric Amant. 2021. “The Mitotic Checkpoint Is a Targetable Vulnerability of Carboplatin-Resistant Triple Negative Breast Cancers.” SCIENTIFIC REPORTS 11. doi:10.1038/s41598-021-82780-6.
Vancouver
1.
Moens S, Zhao P, Baietti MF, Marinelli O, Van Haver D, Impens F, et al. The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers. SCIENTIFIC REPORTS. 2021;11.
IEEE
[1]
S. Moens et al., “The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers,” SCIENTIFIC REPORTS, vol. 11, 2021.
@article{8696396,
  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.}},
  articleno    = {{3176}},
  author       = {{Moens, Stijn and Zhao, Peihua and Baietti, Maria Francesca and Marinelli, Oliviero and Van Haver, Delphi and Impens, Francis and Floris, Giuseppe and Marangoni, Elisabetta and Neven, Patrick and Annibali, Daniela and Sablina, Anna A. and Amant, Frédéric}},
  issn         = {{2045-2322}},
  journal      = {{SCIENTIFIC REPORTS}},
  keywords     = {{Multidisciplinary}},
  language     = {{eng}},
  pages        = {{13}},
  title        = {{The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-82780-6}},
  volume       = {{11}},
  year         = {{2021}},
}

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