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Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition

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Abstract

Although the epidermal growth factor receptor (EGFR) is overexpressed and/or amplified in more than 50 % of all glioblastomas (GBM), therapeutic targeting of the EGFR has not yet been successful. Since histone deacetylases (HDAC) have been described as controlling EGFR expression, we combined the EGFR tyrosine kinase inhibitor erlotinib with different HDAC inhibitors (HDACi) and investigated the benefit of combinatorial therapy for glioblastoma cells. Using representative models of EGFR-amplified, erlotinib-sensitive and -resistant GBM with or without EGFRvIII expression, we determined proliferation, migration, and EGFR-dependent signaling in response to erlotinib and HDACi alone or in combination. HDACi significantly inhibited proliferation of erlotinib-resistant GBM cells, partially restored their sensitivity to erlotinib, and also significantly reduced proliferation of all treatment-naïve cell lines tested. In combination with erlotinib, the development of resistance was prevented. The multitargeted EGFR/HDAC-inhibitor CUDC-101 exhibited similar effects. However, inhibition of cell migration was only achieved by targeting EGFR, and HDACi exhibited no additive effect. Mechanistically, we identified an HDACi-dependent decrease of EGFR/EGFRvIII protein expression underlying the anti-proliferative effects of HDACi. In conclusion, HDACi in combination with erlotinib might serve as a treatment option for newly diagnosed, treatment-naïve tumors irrespective of their EGFR status, as well as for treatment-refractory, EGFR-overexpressing GBM.

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Abbreviations

GBM:

Glioblastoma

EGFR:

Epidermal growth factor receptor

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

TKI:

Tyrosine kinase inhibitor

SEM:

Standard error of the mean

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Acknowledgments

This work was supported by the Forschungs- und Wissenschaftsstiftung Hamburg (MW, KL) and the Deutsche Forschungsgemeinschaft (KL, MW, LA1300/4-1). The authors thank Rossella Galli, Istituto Scientifico H. San Raffaele, Milan for providing the cell lines 0306 and 0627.

Conflict of Interest

K Liffers, K Kolbe, M Westphal, K Lamszus, and A Schulte have no conflicts of interest to declare.

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  1. Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Katrin Liffers, Katarina Kolbe, Manfred Westphal, Katrin Lamszus & Alexander Schulte

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  1. Katrin Liffers
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  2. Katarina Kolbe
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  3. Manfred Westphal
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Correspondence to Alexander Schulte.

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Liffers, K., Kolbe, K., Westphal, M. et al. Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition. Targ Oncol 11, 29–40 (2016). https://doi.org/10.1007/s11523-015-0372-y

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