Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Upcoming)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth
Natividad Pozo, … , Juan M. Sepúlveda, Pilar Sánchez-Gómez
Natividad Pozo, … , Juan M. Sepúlveda, Pilar Sánchez-Gómez
Published May 1, 2013
Citation Information: J Clin Invest. 2013;123(6):2475-2487. https://doi.org/10.1172/JCI63623.
View: Text | PDF
Research Article Oncology

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

  • Text
  • PDF
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.

Authors

Natividad Pozo, Cristina Zahonero, Paloma Fernández, Jose M. Liñares, Angel Ayuso, Masatoshi Hagiwara, Angel Pérez, Jose R. Ricoy, Aurelio Hernández-Laín, Juan M. Sepúlveda, Pilar Sánchez-Gómez

×

Figure 2

DYRK1A is highly expressed in a subset of gliomas and correlates with EGFR expression.

Options: View larger image (or click on image) Download as PowerPoint
DYRK1A is highly expressed in a subset of gliomas and correlates with EG...
(A) DYRK1A transcript levels were determined by RT-PCR in glioma samples and normal tissue (obtained during surgery on epileptic patients). HPRT expression was used for normalization. (B) Correlation between the levels of EGFR and DYRK1A transcription in the GBM samples. Spearman’s rank correlation parameters are presented in the box. (C) Relative DYRK1A expression in EGFR-amplified (amp) and wild-type (WT) GBM samples. (D) IHC images showing an unstained control and 5 representative images of DYRK1A staining of 4 different GBMs. Relative DYRK1A RT-PCR values are shown in the brackets. (E) Low-magnification images of DYRK1A and EGFR staining of 2 different GBMs. Areas of positive (red box) and negative (blue box) staining of both markers are shown at higher magnification. A, astrocytomas. Scale bars: 50 μm. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts