Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells. Clin Cancer Res 2009 Mar 01;15(5):1585-92
Date
02/05/2009Pubmed ID
19190133Pubmed Central ID
PMC2903727DOI
10.1158/1078-0432.CCR-08-2068Scopus ID
2-s2.0-63449122814 (requires institutional sign-in at Scopus site) 85 CitationsAbstract
PURPOSE: The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed.
EXPERIMENTAL DESIGN: To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor-resistant lines relative to the EGFR inhibitor-sensitive lines.
RESULTS: EGFR inhibitor-resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor-resistant lines showed a markedly increased proliferation rate. EGFR inhibitor-resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor-resistant lines. Finally, EGFR inhibitor-resistant lines showed cross-resistance to ionizing radiation.
CONCLUSIONS: We have developed EGFR inhibitor-resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.
Author List
Benavente S, Huang S, Armstrong EA, Chi A, Hsu KT, Wheeler DL, Harari PMAuthor
Kun-Tai Hsu MD Assistant Professor in the Plastic Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Apoptosis
Biomarkers, Tumor
Carcinoma, Squamous Cell
Cell Cycle
Cell Proliferation
Cetuximab
Drug Resistance, Neoplasm
ErbB Receptors
Erlotinib Hydrochloride
Head and Neck Neoplasms
Humans
Immunoblotting
Mice
Mice, Nude
Models, Biological
Neovascularization, Pathologic
Protein Kinase Inhibitors
Quinazolines
Radiation Dosage
Tumor Cells, Cultured
