Molecular correlates of gefitinib responsiveness in human bladder cancer cells
Molecular correlates of gefitinib responsiveness in human bladder cancer cells
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DOI：
10.1158/1535-7163.mct-06-0513
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发表时间：
2007-01-01
影响因子：
5.7
通讯作者：
McConkey, David J.
中科院分区：
文献类型：
--
作者：
Shrader, Marissa;Pino, Maria Simona;McConkey, David J.
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个人类膀胱癌细胞系细胞增殖的影响。吉非替尼在17个品系中的6个品系中以浓度依赖的方式抑制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EGFR依赖细胞在无血清培养基中的基线EGFR、AKT和细胞外信号调节激酶（ERK）磷酸化，而对EGFR独立细胞的基线EGFR或ERK磷酸化没有影响。对候选EGFR依赖性标志物的分析显示，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。与吉非替尼耐药细胞相比，吉非替尼敏感细胞通常表达更高水平的E-cadherin和更低水平的vimentin，但这些相关性并不完美，这表明这些上皮-间质转化的标记物本身不能用于预测egfr依赖性生长。总之，我们的研究结果表明，膀胱癌细胞对EGFR拮抗剂的敏感性具有明显的异质性。尽管表面EGFR水平和上皮-间质转化状态似乎与反应性大致相关，但它们本身不能用于识别对EGFR定向治疗敏感的膀胱肿瘤。然而，比较吉非替尼暴露前后p27（Kip1）或DNA合成水平确实可以识别药物敏感细胞。
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 EGFRindependent 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.