JCI - Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth
Published in Volume 123, Issue 6 (June 3, 2013)
J Clin Invest. 2013;123(6):2475–2487. doi:10.1172/JCI63623.
Copyright © 2013, American Society for Clinical Investigation
Research Article
Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth
1Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain.
2Instituto de Medicina Molecular Aplicada (IMMA), Universidad CEU-San Pablo, Madrid, Spain.
3Brain Tumor Laboratory, Centro Integral Oncológico Clara Campal, Hospital de Madrid, Madrid, Spain.
4Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
5Unidad Multidisciplinar de Neurooncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Address correspondence to: Pilar Sánchez-Gómez, Instituto de Salud Carlos III-UFIEC, Neuro-oncology Unit, Crtra. Majadahonda-Pozuelo, Km 2, Majadahonda, UNK 28922, Spain. Phone: 34918223265; Fax: 34918223269; E-mail: psanchezg@isciii.es.
Authorship note: Natividad Pozo and Cristina Zahonero contributed equally to this work.
First published May 1, 2013
Received for publication January 30, 2013, and accepted in revised form March 1, 2013.
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.
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