Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

J Clin Invest. 2013 Jun;123(6):2475-87. doi: 10.1172/JCI63623. Epub 2013 May 1.

Abstract

Glioblastomas (GBMs) are very aggressive tumors that are resistant to conventional chemo- and radiotherapy. New molecular therapeutic strategies are required to effectively eliminate the subpopulation of GBM tumor-initiating cells that are responsible for relapse. Since EGFR is altered in 50% of GBMs, it represents one of the most promising targets; however, EGFR kinase inhibitors have produced poor results in clinical assays, with no clear explanation for the observed resistance. We uncovered a fundamental role for the dual-specificity tyrosine phosphorylation-regulated kinase, DYRK1A, in regulating EGFR in GBMs. We found that DYRK1A was highly expressed in these tumors and that its expression was correlated with that of EGFR. Moreover, DYRK1A inhibition promoted EGFR degradation in primary GBM cell lines and neural progenitor cells, sharply reducing the self-renewal capacity of normal and tumorigenic cells. Most importantly, our data suggest that a subset of GBMs depends on high surface EGFR levels, as DYRK1A inhibition compromised their survival and produced a profound decrease in tumor burden. We propose that the recovery of EGFR stability is a key oncogenic event in a large proportion of gliomas and that pharmacological inhibition of DYRK1A could represent a promising therapeutic intervention for EGFR-dependent GBMs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / drug effects
  • ErbB Receptors / metabolism*
  • Gene Expression
  • Gene Knockdown Techniques
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Harmine / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology
  • Protein Stability
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proteolysis
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Spheroids, Cellular / pathology
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • RNA, Small Interfering
  • Harmine
  • Dyrk kinase
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases