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Mirk/dyrk1B kinase is upregulated following inhibition of mTOR

Xiaobing Deng1, Jing Hu1, Daina Z Ewton1

  • 1Department of Pathology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Carcinogenesis
|March 5, 2014
PubMed

Insights

Targeting the PI3K/PTEN/Akt/mTOR/p70S6K pathway in cancer can increase Mirk kinase expression. Inhibiting Mirk kinase enhances cancer cell sensitivity to mTOR inhibitors, presenting a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The PI3K/PTEN/Akt/mTOR/p70S6K pathway is frequently deregulated in solid tumors, contributing to drug resistance.
  • Targeting this pathway can paradoxically activate cell survival mediators, necessitating strategies to overcome resistance.

Purpose of the Study:

  • To investigate the regulation of Mirk/dyrk1B kinase by mTOR inhibitors.
  • To explore the potential of Mirk kinase as a therapeutic target to enhance the efficacy of mTOR inhibitors in cancer treatment.

Main Methods:

  • Treatment of cancer cells with various mTOR and Akt inhibitors.
  • Analysis of Mirk/dyrk1B mRNA and protein expression.
  • Investigation of the role of CREB and Akt in Mirk regulation using gene depletion and specific constructs.
  • Assessment of combination therapy using Mirk kinase inhibitors and an mTOR inhibitor (RAD001) in pancreatic and ovarian cancer cell lines.

Main Results:

  • mTOR inhibitors (RAD001, WYE354, rapamycin) significantly upregulated Mirk/dyrk1B expression, while Akt inhibitors had a lesser effect.
  • Mirk mRNA upregulation was mediated by CREB binding to specific promoter sites.
  • CREB depletion reduced Mirk expression, whereas mTOR depletion increased it.
  • An Akt-estrogen receptor construct blocked Mirk mRNA and protein induction.
  • Combined inhibition of Mirk kinase and RAD001 increased the sensitivity of pancreatic and ovarian cancer cells to RAD001.

Conclusions:

  • Mirk/dyrk1B kinase is a downstream mediator of mTOR inhibitor-induced resistance.
  • Targeting Mirk kinase in combination with mTOR inhibitors offers a promising strategy to overcome drug resistance in solid tumors.

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