Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells.
Establishment and characterization of a model of acquired resistance to epidermal growth factor receptor targeting agents in human cancer cells.
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DOI：
10.1158/1078-0432.ccr-08-2068
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发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
Harari PM
中科院分区：
文献类型：
--
作者：
Benavente S;Huang S;Armstrong EA;Chi A;Hsu KT;Wheeler DL;Harari PM
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 FDA approval in oncology. These strategies of EGFR inhibition have demonstrated major tumor regressions in approximately 10–20% of advanced cancer patients. However, many tumors 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 highly needed. To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma (HNSCC) 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. 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, MAPK, AKT and STAT3 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 demonstrated cross resistance to ionizing radiation. We have developed EGFR inhibitor-resistant HNSCC cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.
