Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells
Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells
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DOI：
10.1002/ijc.21290
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发表时间：
2006-01-01
影响因子：
6.4
通讯作者：
Giaccone, G
中科院分区：
文献类型：
--
作者：
Janmaat, ML;Rodriguez, JA;Giaccone, G
在这项研究中，我们研究了一组对吉非替尼具有不同敏感性的非小细胞肺癌细胞株，以激活EGFR、PIK3CA和k-ras突变以及PTEN的基础蛋白表达水平。EGFR突变型NSCLC细胞株H1650以及EGFR野生型细胞株H292和A431对吉非替尼高度敏感，表明其他因素决定了EGFR野生型细胞对吉非替尼的敏感性。在吉非替尼耐药细胞中特异性地检测到激活的k-ras突变，这表明k-ras突变的发生与对EGFR拮抗剂的耐药性有关。在一组细胞系中没有检测到PIK3CA突变，PTEN蛋白表达水平与吉非替尼的敏感性无关。Gefitinib有效地阻断了两个对Gefitinib敏感的NSCLC细胞株中Akt和Erk的磷酸化，进一步支持了我们先前的发现，即PI3K/Akt和/或RAS/Erk通路的持续活性与NSCLC细胞株对Gefitinib的耐药性有关。吉非替尼与mTOR、PI3K、RAS和MEK的特异性抑制剂联合作用于具有EGFR非依赖性PI3K/Akt或RAS/Erk通路活性的NSCLC细胞株。Gefitinib与MEK抑制剂U0126或法尼基转移酶抑制剂SCH66336联合处理的A549细胞和Gefitinib与PI3K抑制剂LY294002联合处理的H460细胞具有相加的细胞毒性，而Gefitinib和雷帕霉素联合处理的H460细胞未观察到相加的细胞毒作用。这些数据表明，联合应用Gefitinib和PI3K/Akt和Ras/Erk通路的特异性抑制剂处理NSCLC细胞可能是一种成功的策略。(C)2005年Wiley-Liss，Inc.
In this study, we have characterized a panel of NSCLC cell lines with differential sensitivity to gefitinib for activating mutations in egfr, pik3ca, and k-ras; and basal protein expression levels of PTEN. The egfr mutant NSCLC cell line H1650 as well as the egfr wild type cell lines H292 and A431 were highly sensitive to gefitinib treatment, indicating that other factors determine gefitinib-sensitivity in egfr wild type cells. Activating k-ras mutations were specifically detected in gefitinib-resistant cells, suggesting that the occurrence of k-ras mutations is correlated with resistance to EGFR antagonists. No pik3ca mutations were detected within the panel of cell lines, and PTEN protein expression levels did not correlate with gefitinib sensitivity. Gefitinib effectively blocked Akt and Erk phosphorylation in two gefitinib-sensitive NSCLC cell lines, further supporting our previous findings that persistent activity of the PI3K/Akt and/or Ras/Erk pathways is associated with gefitinib-resistance of NSCLC cell lines. Gefitinib-resistant NSCLC cell lines, showing EGFR-independent activity of the PI3K/Akt or Ras/Erk pathways, were treated with gefitinib in combination with specific inhibitors of mTOR, PI3K, Ras, and MEK. Additive cytotoxicity was observed in A549 cells co-treated with gefitinib and the MEK inhibitor U0126 or the farnesyl transferase inhibitor SCH66336 and in H460 cells treated with gefitinib and the PI3K inhibitor LY294002, but not in H460 cells treated with gefitinib and rapamycin. These data suggest that combination treatment of NSCLC cells with gefitinib and specific inhibitors of the PI3K/Akt and Ras/Erk pathways may provide a successful strategy. (c) 2005 Wiley-Liss, Inc.