Epidermal growth factor receptor (EGFR)-targeted strategy is limited by resistance. We identify the potential genes involved in EGFR TKI (tyrosine kinase inhibitor) resistance and study the therapeutic mechanism in the non-small cell lung cancers. Potential genes involved in resistance were examined by analyzing datasets from a pair of EGFR TKI-sensitive (PC9) and TKI-resistant cells (PC9/gef). Blood specimens from patients taking EGFR TKI as first-line treatment were used to examine the correlation between drug's efficacy and IL-8 level. The effects of IL-8 on gefitinib-induced apoptosis, stemness, and in vivo tumorigenicity were investigated using established cell lines. We identified IL-8 was up-regulated in gefitinib-resistant cells, and high plasma IL-8 level was correlated with shorter progression-free-survival time. IL-8 overexpression suppressed gefitinib-induced apoptosis in gefitinib-sensitive cells. By contrast, suppression of IL-8 enhanced gefitinib-induced cell death in gefitinib-resistant cells. IL-8 also increased stem-like characteristics including aldehyde dehydrogenase activity, expression of stemness-related genes, clonogenic activity, side-population, and in vivo tumorigenicity. Consistently, knockdown of IL-8 leads to loss of stem cell-like characteristics in gefitinib-resistant cells. Our study demonstrates an important role for IL-8, and suggests IL-8 is a potential therapeutic target for overcoming EGFR TKI resistance.

中文翻译：

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IL-8通过诱导肺癌的干细胞特性赋予对EGFR抑制剂的抗性

靶向表皮生长因子受体（EGFR）的策略受到耐药性的限制。我们确定了涉及EGFR TKI（酪氨酸激酶抑制剂）耐药性的潜在基因，并研究了非小细胞肺癌的治疗机制。通过分析来自一对EGFR TKI敏感（PC9）和TKI耐药细胞（PC9 / gef）的数据集，检查了与耐药相关的潜在基因。使用以EGFR TKI作为一线治疗的患者的血液样本来检查药物疗效与IL-8水平之间的相关性。使用已建立的细胞系研究了IL-8对吉非替尼诱导的细胞凋亡，干性和体内致瘤性的影响。我们发现吉非替尼耐药细胞中IL-8上调，血浆IL-8高水平与较短的无进展生存时间相关。IL-8过表达抑制了吉非替尼敏感细胞中吉非替尼诱导的细胞凋亡。相比之下，IL-8的抑制增强了吉非替尼耐药细胞中吉非替尼诱导的细胞死亡。IL-8还增加了茎样特征，包括醛脱氢酶活性，茎相关基因的表达，克隆形成活性，侧群和体内致瘤性。一致地，IL-8的敲低导致吉非替尼耐药细胞中干细胞样特征的丧失。我们的研究证明了IL-8的重要作用，并暗示IL-8是克服EGFR TKI耐药性的潜在治疗靶标。IL-8还增加了茎样特征，包括醛脱氢酶活性，茎相关基因的表达，克隆形成活性，侧群和体内致瘤性。一致地，IL-8的敲低导致吉非替尼耐药细胞中干细胞样特征的丧失。我们的研究证明了IL-8的重要作用，并暗示IL-8是克服EGFR TKI耐药性的潜在治疗靶标。IL-8还增加了茎样特征，包括醛脱氢酶活性，茎相关基因的表达，克隆形成活性，侧群和体内致瘤性。一致地，IL-8的敲低导致吉非替尼耐药细胞中干细胞样特征的丧失。我们的研究证明了IL-8的重要作用，并暗示IL-8是克服EGFR TKI耐药性的潜在治疗靶标。