2. Academic Validation
  3. The mitotic checkpoint is a targetable vulnerability of carboplatin-resistant triple negative breast cancers

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

  • Sci Rep. 2021 Feb 4;11(1):3176. doi: 10.1038/s41598-021-82780-6.
Stijn Moens 1 2,  Peihua Zhao 1 2,  Maria Francesca Baietti 1 2,  Oliviero Marinelli 2 3,  Delphi Van Haver 4 5 6,  Francis Impens 4 5 6,  Giuseppe Floris 7 8,  Elisabetta Marangoni 9,  Patrick Neven 2 10,  Daniela Annibali  # 2 11,  Anna A Sablina  # 1 2,  Frédéric Amant  # 12 13 14
Affiliations

Affiliations

  • 1 VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
  • 2 Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium.
  • 3 School of Pharmacy, University of Camerino, Camerino, Italy.
  • 4 VIB Center for Medical Biotechnology, Ghent, Belgium.
  • 5 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 6 VIB Proteomics Core, Ghent, Belgium.
  • 7 Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.
  • 8 Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
  • 9 Translational Research Department, Institut Curie, PSL Research University, Paris, France.
  • 10 Department of Obstetrics and Gynecology, University Hospitals Leuven, 3000, Leuven, Belgium.
  • 11 Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 12 Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), 3000, Leuven, Belgium. frederic.amant@uzleuven.be.
  • 13 Department of Obstetrics and Gynecology, University Hospitals Leuven, 3000, Leuven, Belgium. frederic.amant@uzleuven.be.
  • 14 Centre for Gynecologic Oncology Amsterdam (CGOA), Antoni Van Leeuwenhoek-Netherlands Cancer Institute (AvL-NKI), University Medical Center (UMC), Amsterdam, The Netherlands. frederic.amant@uzleuven.be.
  • # Contributed equally.
PMID: 33542435 DOI: 10.1038/s41598-021-82780-6
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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