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Targeting Replicative Stress and DNA Repair by Combining PARP and Wee1 Kinase Inhibitors Is Synergistic in Triple

Xian Chen1, Dong Yang1, Jason P W Carey1

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cancers
|April 30, 2021
PubMed

Insights

High cyclin E levels and BRCA mutations in triple-negative breast cancer (TNBC) predict sensitivity to combined Wee1 and PARP inhibitors. This approach targets replicative stress and DNA repair for synergistic cell killing.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Triple-negative breast cancer (TNBC) lacks specific targets for therapy.
  • Cyclin E deregulation and DNA repair gene mutations (e.g., BRCA1/2) are observed in TNBC.
  • High cyclin E levels correlate with BRCA1/2 mutations and poor prognosis in breast cancer.

Purpose of the Study:

  • To investigate the therapeutic potential of targeting cyclin E and BRCA-mutated TNBC.
  • To evaluate the efficacy of combining a Wee1 kinase inhibitor (AZD-1775) with a PARP inhibitor (MK-4837).

Main Methods:

  • Utilized in vitro and in vivo TNBC models.
  • Assessed the effects of combined AZD-1775 and MK-4837 treatment.
  • Analyzed molecular mechanisms including DNA repair and cell cycle regulation.

Main Results:

  • TNBCs with BRCA1/2 mutations or high cyclin E showed sensitivity to combined Wee1 and PARP inhibition.
  • Combination treatment induced synergistic cell killing.
  • Mechanisms involved replicative stress, DNA repair downregulation, and cytokinesis failure, leading to apoptosis.

Conclusions:

  • Cyclin E and BRCA mutations can serve as biomarkers for identifying TNBC patients likely to benefit from combined Wee1 and PARP inhibitor therapy.
  • This combination strategy holds potential for treating TNBC by exploiting vulnerabilities related to replicative stress and DNA repair deficiencies.
Keywords:
BRCADNA replication stressWee1 kinasecyclin Elow molecular weight cyclin E (LMWE) PARP

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