1. Academic Validation
  2. Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth

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

  • J Clin Invest. 2013 Jun;123(6):2475-87. doi: 10.1172/JCI63623.
Natividad Pozo 1 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
Affiliations

Affiliation

  • 1 Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain.
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.

Figures
Products
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    Product Name
    Description
    Target
    Research Area
  • HY-108476
    99.51%, Dyrk1A And Dyrk1B 抑制剂