PMID- 25189541
OWN - NLM
STAT- MEDLINE
DCOM- 20151110
LR  - 20200930
IS  - 1538-8514 (Electronic)
IS  - 1535-7163 (Linking)
VI  - 13
IP  - 11
DP  - 2014 Nov
TI  - Monensin inhibits epidermal growth factor receptor trafficking and activation: 
      synergistic cytotoxicity in combination with EGFR inhibitors.
PG  - 2559-71
LID - 10.1158/1535-7163.MCT-13-1086 [doi]
AB  - Targeting the EGFR, with inhibitors such as erlotinib, represents a promising 
      therapeutic option in advanced head and neck squamous cell carcinomas (HNSCC). 
      However, they lack significant efficacy as single agents. Recently, we identified 
      the ability of statins to induce synergistic cytotoxicity in HNSCC cells through 
      targeting the activation and trafficking of the EGFR. However, in a phase I trial 
      of rosuvastatin and erlotinib, statin-induced muscle pathology limited the 
      usefulness of this approach. To overcome these toxicity limitations, we sought to 
      uncover other potential combinations using a 1,200 compound screen of 
      FDA-approved drugs. We identified monensin, a coccidial antibiotic, as 
      synergistically enhancing the cytotoxicity of erlotinib in two cell line models 
      of HNSCC, SCC9 and SCC25. Monensin treatment mimicked the inhibitory effects of 
      statins on EGFR activation and downstream signaling. RNA-seq analysis of 
      monensin-treated SCC25 cells demonstrated a wide array of cholesterol and lipid 
      synthesis genes upregulated by this treatment similar to statin treatment. 
      However, this pattern was not recapitulated in SCC9 cells as monensin 
      specifically induced the expression of activation of transcription factor (ATF) 
      3, a key regulator of statin-induced apoptosis. This differential response was 
      also demonstrated in monensin-treated ex vivo surgical tissues in which HMG-CoA 
      reductase expression and ATF3 were either not induced, induced singly, or both 
      induced together in a cohort of 10 patient samples, including four HNSCC. These 
      results suggest the potential clinical utility of combining monensin with 
      erlotinib in patients with HNSCC.
CI  - (c)2014 American Association for Cancer Research.
FAU - Dayekh, Khalil
AU  - Dayekh K
AD  - Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The 
      University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine and the 
      Department of Biochemistry, The University of Ottawa, Ottawa, Ontario, Canada.
FAU - Johnson-Obaseki, Stephanie
AU  - Johnson-Obaseki S
AD  - Department of Otolaryngology, The Ottawa Hospital, Ottawa, Ontario, Canada.
FAU - Corsten, Martin
AU  - Corsten M
AD  - Department of Otolaryngology, The Ottawa Hospital, Ottawa, Ontario, Canada.
FAU - Villeneuve, Patrick J
AU  - Villeneuve PJ
AD  - Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The 
      University of Ottawa, Ottawa, Ontario, Canada. Department of Thoracic Surgery, 
      The Ottawa Hospital, Ottawa, Ontario, Canada.
FAU - Sekhon, Harmanjatinder S
AU  - Sekhon HS
AD  - Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, 
      Ontario, Canada.
FAU - Weberpals, Johanne I
AU  - Weberpals JI
AD  - Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The 
      University of Ottawa, Ottawa, Ontario, Canada. Department of Gynaecologic 
      Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada.
FAU - Dimitroulakos, Jim
AU  - Dimitroulakos J
AD  - Centre for Cancer Therapeutics, the Ottawa Hospital Research Institute, The 
      University of Ottawa, Ottawa, Ontario, Canada. Faculty of Medicine and the 
      Department of Biochemistry, The University of Ottawa, Ottawa, Ontario, Canada. 
      jdimitroulakos@ohri.ca.
LA  - eng
GR  - MOP-311725/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140904
PL  - United States
TA  - Mol Cancer Ther
JT  - Molecular cancer therapeutics
JID - 101132535
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 906O0YJ6ZP (Monensin)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Squamous Cell/*drug therapy/enzymology/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Drug Synergism
MH  - ErbB Receptors/*antagonists & inhibitors/metabolism
MH  - Erlotinib Hydrochloride
MH  - Head and Neck Neoplasms/*drug therapy/enzymology/metabolism/pathology
MH  - Humans
MH  - Monensin/administration & dosage/*pharmacology
MH  - Protein Kinase Inhibitors/administration & dosage/*pharmacology
MH  - Quinazolines/administration & dosage/*pharmacology
MH  - Signal Transduction
MH  - Squamous Cell Carcinoma of Head and Neck
EDAT- 2014/09/06 06:00
MHDA- 2015/11/11 06:00
CRDT- 2014/09/06 06:00
PHST- 2014/09/06 06:00 [entrez]
PHST- 2014/09/06 06:00 [pubmed]
PHST- 2015/11/11 06:00 [medline]
AID - 1535-7163.MCT-13-1086 [pii]
AID - 10.1158/1535-7163.MCT-13-1086 [doi]
PST - ppublish
SO  - Mol Cancer Ther. 2014 Nov;13(11):2559-71. doi: 10.1158/1535-7163.MCT-13-1086. 
      Epub 2014 Sep 4.