title: Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition.
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.
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Liffers
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Kolbe
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. aschulte@uke.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D056572:Histone Deacetylase Inhibitors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C410723:epidermal growth factor receptor VIII; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors