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

Stijn Moens1,2, Peihua Zhao1,2, Maria Francesca Baietti1,2

  • 1VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.

Scientific Reports
|February 5, 2021
PubMed

Insights

Triple-negative breast cancer (TNBC) develops resistance to carboplatin chemotherapy. Inhibiting CHEK1 re-sensitizes resistant TNBC cells, offering a new treatment strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Triple-negative breast cancer (TNBC) is aggressive and lacks effective therapies.
  • Carboplatin chemotherapy is effective but resistance develops, necessitating new treatment approaches.
  • Understanding carboplatin resistance mechanisms is crucial for improving TNBC treatment outcomes.

Purpose of the Study:

  • To identify vulnerabilities in carboplatin-resistant TNBC.
  • To investigate the role of metabolism and the mitotic checkpoint in carboplatin resistance.
  • To evaluate CHEK1 inhibition as a strategy to overcome carboplatin resistance in TNBC.

Main Methods:

  • Generation of carboplatin-resistant TNBC cell lines and patient-derived xenografts.
  • Mass spectrometry-based proteome profiling to analyze resistance mechanisms.
  • Kinome shRNA screening to identify vulnerabilities and essential survival pathways.
  • Pharmacological inhibition of CHEK1 using prexasertib in combination with carboplatin.

Main Results:

  • Carboplatin resistance in TNBC is associated with metabolic rewiring and enhanced anti-oxidative responses.
  • Resistant cells exhibit dysregulation of the mitotic checkpoint and are vulnerable to its abrogation.
  • CHEK1 and WEE1 are essential for the survival of carboplatin-resistant TNBC cells.
  • Combined treatment with prexasertib and carboplatin suppressed tumor growth in resistant xenografts and was well-tolerated.

Conclusions:

  • Abrogation of the mitotic checkpoint via CHEK1 inhibition re-sensitizes carboplatin-resistant TNBC to carboplatin.
  • Targeting CHEK1 in combination with carboplatin is a promising therapeutic strategy for treating resistant TNBC.
  • This approach offers a potential new avenue for managing aggressive and treatment-resistant breast cancer.

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