Document Detail


Preclinical modeling of EGFR inhibitor resistance in head and neck cancer.
MedLine Citation:
PMID:  22785204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The epidermal growth factor receptor (EGFR) is widely expressed in head and neck squamous cell carcinomas (HNSCC) and can activate many growth and survival pathways within tumor cells. Despite ubiquitous EGFR expression, therapies targeting the receptor are only modestly effective in the treatment of HNSCC. A consistent mechanism of resistance to EGFR targeting agents has not yet been identified in HNSCC likely due, in part, to the paucity of preclinical models. We assessed the in vitro and in vivo responses of a panel of 10 genotypically validated HNSCC cell lines to the EGFR inhibitors erlotinib and cetuximab to determine their validity as models of resistance to these agents. We defined a narrow range of response to erlotinib in HNSCC cells in vitro and found a positive correlation between EGFR protein expression and erlotinib response. We observed cross-sensitivity in one HNSCC cell line, 686LN, between erlotinib and cetuximab in vivo. We attempted to generate models of cetuximab resistance in HNSCC cell line-derived xenografts and heterotopic tumorgrafts generated directly from primary patient tumors. While all 10 HNSCC cell line xenografts tested were sensitive to cetuximab in vivo, heterotopic patient tumorgrafts varied in response to cetuximab indicating that these models may be more representative of clinical responses. These studies demonstrate the limitations of using HNSCC cell lines to reflect the heterogeneous clinical responses to erlotinib and cetuximab, and suggest that different approaches including heterotopic tumorgrafts may prove more valuable to elucidate mechanisms of clinical resistance to EGFR inhibitors in HNSCC.
Authors:
Kelly M Quesnelle; Sarah E Wheeler; Mary K Ratay; Jennifer R Grandis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-08-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  13     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-03     Completed Date:  2012-12-14     Revised Date:  2013-08-12    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  935-45     Citation Subset:  IM    
Affiliation:
Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies, Monoclonal / administration & dosage,  pharmacology*
Antineoplastic Agents / administration & dosage,  pharmacology*
Carcinoma, Squamous Cell / drug therapy*,  metabolism
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Head and Neck Neoplasms / drug therapy*,  metabolism
Humans
Inhibitory Concentration 50
Mice
Mice, Nude
Protein Kinase Inhibitors / administration & dosage,  pharmacology*
Quinazolines / administration & dosage,  pharmacology*
Receptor, Epidermal Growth Factor / antagonists & inhibitors*,  metabolism
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
F31DE020947/DE/NIDCR NIH HHS; P30CA047904/CA/NCI NIH HHS; P50CA097190/CA/NCI NIH HHS; R01CA098372/CA/NCI NIH HHS; T32GM08424/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antineoplastic Agents; 0/Protein Kinase Inhibitors; 0/Quinazolines; EC 2.7.10.1/Receptor, Epidermal Growth Factor; J4T82NDH7E/erlotinib; PQX0D8J21J/cetuximab
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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