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  • Title: [Molecular mechanism of erlotinib resistance in epidermal growth factor receptor mutant non-small cell lung cancer cell line H1650].
    Author: Han R, Wang X, Zhong D, Zhao J, Chen Z, Sun L, Wang J, Zhang J.
    Journal: Zhongguo Fei Ai Za Zhi; 2012 Dec; 15(12):689-93. PubMed ID: 23249714.
    Abstract:
    BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression and mutations were existed in more than 40% of the lung cancer, and it's the one of molecular targets in clinical treatment. But the EGFR tyrosine kinase inhibitors (TKI)-resistance is becoming a challenging clinical problem as following the application of EGFR-TKIs, Gefitinib or Erlotinib. However, the mechanistic explanation for resistance in the some cases is still lacking. Here we researched the resistance mechanism of H1650 cells. METHODS: Using real-time RT-PCR to analyze the EGFR mRNA expression level in EGFR wild-type non-small cell lung cancer (NSCLC) cells; MTT analysis detected the cytotoxicity for NSCLC cells to Erlotinib; Western blot analysis examined the mutant situations and the downstream signaling protein phosphorylation level in EGFR-mutant NSCLC cells with the treatment of Erlotinib or/and PI3K inhibitor, LY294002. RESULTS: In the EGFR wild-type NSCLC cells, the expression level of EGFR mRNA varied dramatically and all the cells showed resistant to Erlotinib; In the EGFR-mutant cells, HCC827 and H1650 (the same activating-mutation type), HCC827 cells were Erlotinib-sensitive as well as H1650 demonstrated primary relative resistance. Western blot analysis showed the loss of PTEN and the p-AKT level was not inhibited with the treatment of Erlotinib or/and LY294002 in H1650 cells, while HCC827 cells were no PTEN loss and definitively decrease of p-AKT level. CONCLUSIONS: EGFR wild-type NSCLC cells were resistant to Erlotinib no matter of how EGFR mRNA expression level. EGFR-activating mutations correlated with responses to Erlotinib. The PTEN loss and activation of AKT signaling pathway contributed to Erlotinib resistance in EGFR-mutant NSCLC cell line H1650. 背景与目的: 表皮生长因子受体（epidermal growth factor receptor, EGFR）高表达和突变与40%左右的肺癌有关，已成为靶向治疗药物研究热点；随着Gefitinib和Erlotinib作为EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitor, TKI）代表药物应用于临床，继而产生的耐药现象亦成为临床一大难题，部分耐药机制仍不清楚。本研究探讨非小细胞肺癌（non-small cell lung cancer, NSCLC）细胞系H1650耐药机制。 方法: 选用real-time RT-PCR检测EGFR野生型NSCLC细胞系中EGFR mRNA表达水平；MTT检测癌细胞对Erlotinib的药物敏感性；Western blot检测EGFR突变NSCLC细胞系突变情况和Erlotinib及PI3K抑制剂（LY294002）对EGFR突变型NSCLC细胞下游信号蛋白磷酸化水平的影响。 结果: EGFR野生型细胞系中，EGFR mRNA表达水平高低不一，但均对Erlotinib耐药；EGFR突变型细胞系中，HCC827和H1650为同种突变类型，HCC827对Erlotinib敏感，H1650则相对耐药；检测显示，H1650细胞中PTEN表达缺失，给予Erlotinib和LY294002处理后，HCC827中p-AKT明显被抑制，但H1650中p-AKT下调不明显。 结论: 在NSCLC细胞系中，Erlotinib药物敏感性与EGFR的mRNA表达高低无关，但与EGFR的突变类型有关；H1650对Erlotinib相对耐药可能与PTEN缺失导致的p-AKT持续活化有关。
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