Benavente Sergio, Huang Shyhmin, Armstrong Eric A, Chi Alexander, Hsu Kun-Tai, Wheeler Deric L, Harari Paul M
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792-0600, USA.
Clin Cancer Res. 2009 Mar 1;15(5):1585-92. doi: 10.1158/1078-0432.CCR-08-2068. Epub 2009 Feb 3.
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.
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.
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.
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.
表皮生长因子受体（EGFR）被认为是多种人类肿瘤增殖和进展的关键介质。一系列EGFR特异性抑制剂最近已获得美国食品药品监督管理局在肿瘤学领域的批准。这些EGFR抑制策略在大约10%至20%的晚期癌症患者中显示出显著的肿瘤消退。然而，许多肿瘤最终会对治疗产生耐药性。因此，迫切需要更好地了解获得性EGFR抑制剂耐药的潜在机制以及克服耐药性的潜在策略。
为了开发对EGFR抑制剂具有获得性耐药的细胞系，我们使用了人头颈部鳞状细胞癌肿瘤细胞系SCC-1。用递增浓度的西妥昔单抗、吉非替尼或厄洛替尼处理细胞，并对EGFR抑制剂耐药细胞系相对于EGFR抑制剂敏感细胞系的分子变化进行表征。
EGFR抑制剂耐药细胞系在无药培养基和无胸腺裸鼠异种移植模型中均能维持其耐药表型。此外，EGFR抑制剂耐药细胞系的增殖率显著增加。EGFR抑制剂耐药细胞系中磷酸化EGFR、丝裂原活化蛋白激酶、AKT以及信号转导子和转录激活子3的水平升高，这与凋亡能力降低有关。随后的体内实验表明，EGFR抑制剂耐药细胞系的血管生成潜力增强。最后，EGFR抑制剂耐药细胞系对电离辐射表现出交叉耐药性。
我们已开发出对EGFR抑制剂耐药的人头颈部鳞状细胞癌细胞系。该模型为研究获得性EGFR阻断耐药的分子机制提供了有价值的临床前工具。
