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Transcriptional Regulation of Protein Synthesis by Mediator Kinase Represents a Therapeutic Vulnerability in

Dong Wang1,2, Caitlin Ritz1, Angela Pierce1,2

  • 1Department of Pediatrics, University of Colorado Anschutz Medical Campus; Aurora, CO, USA.

Research Square
|November 22, 2024
PubMed

Insights

Cyclin-dependent kinase 8 (CDK8) inhibition halts MYC-driven medulloblastoma growth by reducing MYC expression and protein synthesis. Combining CDK8 and mTOR inhibitors offers a synergistic therapeutic strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor with poor prognosis.
  • Current treatment options for MYC-driven MB are limited, necessitating novel therapeutic strategies.
  • The role of specific kinases in regulating MYC-driven MB pathogenesis remains incompletely understood.

Purpose of the Study:

  • To identify novel regulators of MYC-driven medulloblastoma using CRISPR-Cas9 screening.
  • To elucidate the functional role of CDK8 in MYC-driven MB.
  • To evaluate the therapeutic potential of targeting CDK8, alone and in combination with mTOR inhibitors.

Main Methods:

  • CRISPR-Cas9 screening was performed on MYC-driven medulloblastoma cell lines.
  • RNA polymerase II occupancy, gene transcription, ribosome biogenesis, and protein synthesis were analyzed.
  • Therapeutic efficacy was assessed using *in vivo* and *in vitro* models, including combination therapy with mTOR inhibitors.

Main Results:

  • CDK8 was identified as a critical regulator of MYC-driven MB.
  • CDK8 inhibition led to decreased MYC expression, suppressed ribosome biogenesis, and reduced protein synthesis, inhibiting tumor growth.
  • CDK8 regulates RNA polymerase II occupancy at ribosomal gene loci, impacting epigenetic modifications.
  • Combined inhibition of CDK8 and mTOR synergistically enhanced therapeutic outcomes in preclinical models.
  • Targeting CDK8 diminished stem-like neoplastic cells with hyperactive ribosome biogenesis.

Conclusions:

  • CDK8 is a key mediator of MYC-driven medulloblastoma, linking transcriptional regulation to mRNA translation.
  • Targeting CDK8 represents a promising therapeutic strategy for MYC-driven MB by inhibiting protein synthesis.
  • Combination therapy with CDK8 and mTOR inhibitors offers a synergistic approach to optimize treatment for this aggressive cancer.

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