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CDK5 Inhibition Abrogates TNBC Stem-Cell Property and Enhances Anti-PD-1 Therapy

Yuncheng Bei1, Nan Cheng1, Ting Chen1,2

  • 1State Key Laboratory of Pharmaceutical Biotechnology and The Comprehensive Cancer Center Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing University Nanjing 210046 P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 26, 2020
PubMed

Insights

Targeting CDK5 in triple-negative breast cancer (TNBC) reduces cancer stem cells and enhances anti-PD-1 therapy. This approach diminishes stemness and reverses the immunosuppressive tumor microenvironment for better treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Triple-negative breast cancer (TNBC) is aggressive, linked to cancer stem cells (CSCs) and poor prognosis.
  • Aberrant CDK5 activation is associated with TNBC progression and poor clinical outcomes.

Purpose of the Study:

  • To investigate the role of CDK5 in TNBC stemness and its impact on therapeutic response.
  • To explore CDK5 as a therapeutic target for diminishing stemness and enhancing anti-PD-1 efficacy in TNBC.

Main Methods:

  • Investigated CDK5-mediated phosphorylation of PPARγ at Ser273.
  • Analyzed CD44 isoform switching (CD44s to CD44v) and its effect on TNBC stemness.
  • Utilized a TNBC mouse model to assess the impact of blocking CDK5/p-PPARγ on metastasis.
  • Evaluated the effect of diminishing stemness on the tumor microenvironment and anti-PD-1 therapy response.
  • Elucidated the mechanism of CDK5 in regulating PPARγ E3 ligase activity and ESRP1 stability.

Main Results:

  • CDK5 phosphorylates PPARγ, inducing CD44v isoform switching and increasing TNBC stemness.
  • Blocking CDK5/p-PPARγ reduced CD44v+ CSCs and abrogated metastasis in a TNBC mouse model.
  • Diminishing stemness reversed the immunosuppressive tumor microenvironment.
  • Targeting CDK5 enhanced the efficacy of anti-PD-1 therapy in TNBC.
  • CDK5 regulates PPARγ's E3 ubiquitin ligase activity and protects ESRP1 from proteolysis.

Conclusions:

  • CDK5 blockade is a potent strategy to reduce stemness transformation in TNBC.
  • Targeting CDK5 can enhance the response to PD-1 blockade in TNBC therapy by reversing immunosuppression.
Keywords:
CD44 variantsCDK5PPARγ phosphorylationcancer stem cellsimmune checkpoint blockadetriple‐negative breast cancertumor microenvironment

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