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Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities

Donald C Porter1, Elena Farmaki, Serena Altilia

  • 1Senex Biotechnology, Inc., Columbia, SC 29208, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 8, 2012
PubMed

Insights

Chemotherapy can paradoxically promote tumor growth by altering gene expression. This study identifies CDK8 inhibition as a strategy to block this effect and enhance chemotherapy efficacy, improving patient survival outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Conventional chemotherapy can induce a pro-tumorigenic secretory phenotype in damaged tissues.
  • This phenotype is partly mediated by the cell-cycle inhibitor p21 (CDKN1A).

Purpose of the Study:

  • To develop small molecules that inhibit damage-induced transcription downstream of p21.
  • To investigate the role of CDK8 and CDK19 in mediating chemotherapy-induced tumor support.

Main Methods:

  • Development of small-molecule inhibitors targeting CDK8/CDK19.
  • Analysis of p21 binding and functional cooperation with CDK8.
  • Assessment of CDK8 inhibitor efficacy in preclinical cancer models (in vitro and in vivo).
  • Correlation analysis of CDK8 expression with patient survival data.

Main Results:

  • p21 directly binds and activates CDK8, promoting internucleolar body formation.
  • CDK8 inhibition suppresses tumor-promoting paracrine activities induced by chemotherapy.
  • CDK8 inhibition reverses chemotherapy-induced increases in tumor engraftment and serum mitogenic activity.
  • CDK8 inhibitors enhance chemotherapy efficacy against mixed tumor cell/fibroblast xenografts.
  • High CDK8 expression correlates with poor survival in breast and ovarian cancers.

Conclusions:

  • CDK8 inhibition is a viable strategy to counteract chemotherapy-induced tumor support.
  • Targeting CDK8 can improve the effectiveness of cancer chemotherapy.
  • CDK8 represents a promising therapeutic target for enhancing cancer treatment outcomes.

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