Inhibition of DYRK1A destabilizes EGFR and reduces EGFR-dependent glioblastoma growth
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
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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Research Article Oncology

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

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 7

DYRK1A inhibition stimulates EGFR lysosomal degradation and termination of EGF signaling.

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DYRK1A inhibition stimulates EGFR lysosomal degradation and termination ...
Western blot analysis of SVZ-NSCs (A) or U87 cells (B) that were deprived of growth factors for 12 hours and then exposed to EGF for the indicated durations in the presence or absence of harmine. Quantification of EGFR levels relative to β-actin is shown in the bottom graphs. (C) Western blot analysis of the EGFR signaling pathway after EGF stimulation of 2 different GBM-TIC lines in the presence or absence of harmine. Quantification of EGFR, p-AKT, and p-ERK1/2 levels relative to β-actin is shown on the right. (D) GBM-TICs were preincubated in the presence or absence of harmine. Four hours later, EGF Alexa488 was added and the cells were fixed at t = 0 or t = 1 hour, 30 minutes. Representative confocal images of EGFR lysosomal targeting in GBM4 cells are shown. Quantification of the yellow dots for 2 different GBM-TIC lines is represented by the graph on the right. *P ≤ 0.05. Scale bar: 25 μm.