PMID- 26032687
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20181202
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Linking)
VI  - 11
IP  - 1
DP  - 2016 Feb
TI  - Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, 
      Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition.
PG  - 29-40
LID - 10.1007/s11523-015-0372-y [doi]
AB  - 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-naive 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-naive tumors irrespective of 
      their EGFR status, as well as for treatment-refractory, EGFR-overexpressing GBM.
FAU - Liffers, Katrin
AU  - Liffers K
AD  - Laboratory for Brain Tumor Biology, Department of Neurosurgery, University 
      Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
FAU - Kolbe, Katarina
AU  - Kolbe K
AD  - Laboratory for Brain Tumor Biology, Department of Neurosurgery, University 
      Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
FAU - Westphal, Manfred
AU  - Westphal M
AD  - Laboratory for Brain Tumor Biology, Department of Neurosurgery, University 
      Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
FAU - Lamszus, Katrin
AU  - Lamszus K
AD  - Laboratory for Brain Tumor Biology, Department of Neurosurgery, University 
      Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
FAU - Schulte, Alexander
AU  - Schulte A
AD  - Laboratory for Brain Tumor Biology, Department of Neurosurgery, University 
      Hospital Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. 
      aschulte@uke.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (epidermal growth factor receptor VIII)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - ErbB Receptors/*antagonists & inhibitors/genetics/metabolism
MH  - Erlotinib Hydrochloride/*pharmacology
MH  - Glioblastoma/*drug therapy/metabolism/pathology
MH  - Histone Deacetylase Inhibitors/*pharmacology
MH  - Humans
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - RNA, Messenger/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Tumor Cells, Cultured
EDAT- 2015/06/03 06:00
MHDA- 2016/12/15 06:00
CRDT- 2015/06/03 06:00
PHST- 2015/06/03 06:00 [entrez]
PHST- 2015/06/03 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 10.1007/s11523-015-0372-y [pii]
AID - 10.1007/s11523-015-0372-y [doi]
PST - ppublish
SO  - Target Oncol. 2016 Feb;11(1):29-40. doi: 10.1007/s11523-015-0372-y.