Department of Pharmaceutical Oncology and Laboratory of Molecular Cancer Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Cancer Res. 2010 Nov 1;70(21):8715-25. doi: 10.1158/0008-5472.CAN-10-0043. Epub 2010 Oct 19.
Gefitinib (Iressa) and erlotinib (Tarceva), which target the epidermal growth factor receptor (EGFR), are approved for treatment of patients with advanced non-small cell lung cancer (NSCLC). Patients whose tumors harbor mutations in the EGFR gene, including delE746-A750 in exon 19 and L858R in exon 21, may benefit in particular from gefitinib treatment. However, acquired resistance to gefitinib has been a serious clinical problem, and further optimization is needed for application of EGFR-targeted drugs in lung cancer patients. In this study, we established gefitinib-resistant NSCLC cells from PC-9 cell line, which harbors the delE746-A750 mutation, by exposing the cell line to gefitinib for over 7 months. Gefitinib-resistant PC-9/GEFs cell lines showed a marked downregulation of PTEN expression and increased Akt phosphorylation. In revertant, gefitinib-sensitive clones (PC-9/Rev) derived from PC-9/GEF1-1 and PC-9/GEF2-1, PTEN expression, as well as sensitivity to gefitinib and erlotinib, was restored. Knockdown of PTEN expression using small interfering RNA specific for PTEN in PC-9 cells resulted in drug resistance to gefitinib and erlotinib. Nuclear translocation of the EGR1 transcription factor, which regulates PTEN expression, was shown to be suppressed in resistant clones and restored in their revertant clones. Reduced PTEN expression was also seen in tumor samples from a patient with gefitinib-refractory NSCLC. This study thus strongly suggests that loss of PTEN expression contributes to gefitinib and erlotinib resistance in NSCLC. Our findings reinforce the therapeutic importance of PTEN expression in the treatment of NSCLC with EGFR-targeted drugs.
吉非替尼（Iressa）和厄洛替尼（Tarceva）针对表皮生长因子受体（EGFR），被批准用于治疗晚期非小细胞肺癌（NSCLC）患者。肿瘤中 EGFR 基因发生突变的患者，包括外显子 19 的 delE746-A750 和外显子 21 的 L858R，可能特别受益于吉非替尼治疗。然而，吉非替尼获得性耐药一直是一个严重的临床问题，需要进一步优化 EGFR 靶向药物在肺癌患者中的应用。在这项研究中，我们通过将细胞系暴露于吉非替尼超过 7 个月，从携带 delE746-A750 突变的 PC-9 细胞系中建立了吉非替尼耐药的 NSCLC 细胞系。吉非替尼耐药的 PC-9/GEFs 细胞系表现出 PTEN 表达明显下调和 Akt 磷酸化增加。在回复突变体中，源自 PC-9/GEF1-1 和 PC-9/GEF2-1 的吉非替尼敏感克隆（PC-9/Rev）中，PTEN 表达以及对吉非替尼和厄洛替尼的敏感性得到恢复。在 PC-9 细胞中使用针对 PTEN 的小干扰 RNA 敲低 PTEN 表达导致对吉非替尼和厄洛替尼的耐药性。调节 PTEN 表达的 EGR1 转录因子的核易位在耐药克隆中受到抑制，并在其回复突变体克隆中得到恢复。在一名吉非替尼难治性 NSCLC 患者的肿瘤样本中也观察到 PTEN 表达减少。因此，本研究强烈表明 PTEN 表达缺失导致 NSCLC 对吉非替尼和厄洛替尼的耐药性。我们的发现加强了 PTEN 表达在 EGFR 靶向药物治疗 NSCLC 中的治疗重要性。
