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Therapeutic Rationale to Target Highly Expressed CDK7 Conferring Poor Outcomes in Triple-Negative Breast Cancer

Bo Li1, Triona Ni Chonghaile2, Yue Fan1

  • 1UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

Cancer Research
|April 30, 2017
PubMed

Insights

Triple-negative breast cancer (TNBC) has poor prognosis. Cell-cycle-related kinase CDK7 is a therapeutic target, with high CDK7 expression linked to poor outcomes. Combining CDK7 and BCL-2/BCL-XL inhibitors shows promise for TNBC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Triple-negative breast cancer (TNBC) presents significant challenges due to poor prognosis and high relapse rates.
  • Current therapeutic strategies lack specific biomarkers and effective targeted treatments for TNBC.
  • Identifying novel therapeutic targets and biomarkers is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of cell-cycle-related kinase 7 (CDK7) as a potential biomarker and therapeutic target in TNBC.
  • To evaluate the efficacy of CDK7 inhibitors, alone and in combination with BCL-2/BCL-XL inhibitors, in preclinical TNBC models.

Main Methods:

  • Analysis of publicly available transcriptomic data from TNBC patient cohorts (n=383 and n=217) to assess CDK7 mRNA levels and patient prognosis.
  • Validation of high CDK7 protein expression association with poor prognosis in RATHER (n=109) and METABRIC (n=203) TNBC cohorts.
  • Assessment of CDK7 kinase inhibitors (BS-181, THZ1) on RNA polymerase II phosphorylation and transcriptional inhibition in TNBC cells.
  • Evaluation of synergistic effects of combining CDK7 inhibitor THZ1 with BCL-2/BCL-XL inhibitors (ABT-263/ABT199) on TNBC cell growth and apoptosis.

Main Results:

  • Elevated CDK7 mRNA levels correlated with poorer patient prognosis in analyzed TNBC datasets.
  • High CDK7 protein expression was significantly associated with poor prognosis in independent TNBC patient cohorts.
  • CDK7 inhibitors (THZ1, BS-181) demonstrated transcriptional inhibition, with THZ1 showing superior potency.
  • Combination therapy of THZ1 with BCL-2/BCL-XL inhibitors synergistically induced growth inhibition and apoptosis in human TNBC cells.

Conclusions:

  • Elevated CDK7 expression serves as a potential biomarker for poor prognosis in triple-negative breast cancer.
  • Targeting CDK7, particularly with potent inhibitors like THZ1, represents a viable therapeutic strategy for TNBC.
  • Combining CDK7 inhibitors with BCL-2/BCL-XL inhibitors offers a promising, mechanism-based approach to enhance TNBC treatment efficacy.

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