Shrader Marissa, Pino Maria Simona, Brown Gordon, Black Peter, Adam Liana, Bar-Eli Menahse, Dinney Colin P N, McConkey David J
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Unit 173, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Mol Cancer Ther. 2007 Jan;6(1):277-85. doi: 10.1158/1535-7163.MCT-06-0513.
We characterized the effects of the small molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) on cell proliferation in a panel of 17 human bladder cancer cell lines. Gefitinib inhibited DNA synthesis in a concentration-dependent fashion in 6 of 17 lines. Growth inhibition was associated with p27(Kip1) accumulation and decreased cyclin-dependent kinase 2 activity. Gefitinib also inhibited baseline EGFR, AKT, and extracellular signal-regulated kinase (ERK) phosphorylation in the EGFR-dependent cells maintained in serum-free medium, whereas it had no effect on baseline EGFR or ERK phosphorylation in the EGFR-independent cells. Analyses of candidate markers of EGFR dependency revealed that the gefitinib-sensitive cells expressed higher surface EGFR levels than the gefitinib-resistant lines. Gefitinib-sensitive cells generally expressed higher levels of E-cadherin and lower levels of vimentin than the gefitinib-resistant cells, but these correlations were not perfect, suggesting that these markers of epithelial-mesenchymal transition cannot be used by themselves to prospectively predict EGFR-dependent growth. Together, our results show that bladder cancer cells are markedly heterogeneous with respect to their sensitivity to EGFR antagonists. Although surface EGFR levels and epithelial-mesenchymal transition status seem to roughly correlate with responsiveness, they cannot be used by themselves to identify bladder tumors that will be sensitive to EGFR-directed therapy. However, comparing levels of p27(Kip1) or DNA synthesis before and after gefitinib exposure does identify the drug-sensitive cells.
我们研究了小分子表皮生长因子受体（EGFR）抑制剂吉非替尼（ZD1839，易瑞沙）对17种人膀胱癌细胞系细胞增殖的影响。吉非替尼在17种细胞系中的6种中以浓度依赖性方式抑制DNA合成。生长抑制与p27（Kip1）积累和细胞周期蛋白依赖性激酶2活性降低有关。吉非替尼还抑制了无血清培养基中培养的EGFR依赖性细胞的基线EGFR、AKT和细胞外信号调节激酶（ERK）磷酸化，而对EGFR非依赖性细胞的基线EGFR或ERK磷酸化没有影响。对EGFR依赖性候选标志物的分析表明，吉非替尼敏感细胞比吉非替尼耐药细胞系表达更高的表面EGFR水平。吉非替尼敏感细胞通常比吉非替尼耐药细胞表达更高水平的E-钙黏蛋白和更低水平的波形蛋白，但这些相关性并不完美，这表明这些上皮-间质转化标志物不能单独用于前瞻性预测EGFR依赖性生长。总之，我们的结果表明，膀胱癌细胞对EGFR拮抗剂的敏感性存在显著异质性。虽然表面EGFR水平和上皮-间质转化状态似乎与反应性大致相关，但它们不能单独用于识别对EGFR导向治疗敏感的膀胱肿瘤。然而，比较吉非替尼暴露前后p27（Kip1）水平或DNA合成确实可以识别药物敏感细胞。
