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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.
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Research Article Oncology

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

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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

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Figure 8

SPRY2 overexpression reverses the effect of harmine on EGFR degradation and GBM-TIC self-renewal.

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SPRY2 overexpression reverses the effect of harmine on EGFR degradation ...
(A) GBM5-TICs were infected with control or SPRY2-expressing retrovirus and 48 hours later, the cells were analyzed by Western blotting. (B) Control or SPRY2-expressing GBM5-TICs were deprived of growth factors for 12 hours and then EGF was added in the presence of harmine for the indicated durations. EGFR in the cells was analyzed by Western blotting. (C) Twenty-four hours after retroviral infection of GBM5-TICs, the cells were incubated in the presence or absence of harmine for 3 days. Dissociated cells were plated in the absence of the drug, and the number of secondary spheres formed was counted. ***P ≤ 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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