EGFR-TKI的原发和继发性耐药已成为其在肺癌治疗中应用的瓶颈。我们前期研究发现Derlin-1在EGFR-TKI耐药细胞系中高表达，吉非替尼处理能够上调EGFR突变细胞内Derlin-1的表达水平，转染Derlin-1能够减弱吉非替尼对肿瘤细胞增殖的抑制并且能够上调Akt的活性，表明 Derlin-1可能通过Akt途径使肺癌细胞产生EGFR-TKI耐药，但Derlin-1激活Akt的分子机制及是否还通过其他途径介导耐药目前还不清楚。 本研究拟双向调控肺癌细胞中Derlin-1的表达，采用基因芯片、抗体芯片、免疫共沉淀、GST-pulldown等明确Derlin-1介导Akt通路激活的关键因子，揭示Derlin-1致耐药的机制。结合动物实验和临床肺癌标本揭示Derlin-1表达对EGFR-TKI靶向治疗敏感性的诊断预测作用。

EGFR-TKI resistance significantly limits its use in clinical practice. We found that Derlin-1 was overexpressed in lung cancer cell lines with EGFR-TKI resistance. Gefitinib treatment upregulated Derlin-1 levels in lung cancer cells haboring EGFR mutation. Derlin-1 transfection could alleviate the effect of gefitinib on cell growth inhibition and upregulated Akt activity, indicating the role of Akt pathway in Derlin-1 mediated EGFR-TKI resistance. However, its molecular mechanism still needs to be explored. In this study, we will upregulate and knockdown Derlin-1 expression in lung cancer cells and use gene chip, antibody microarray, immunoprecipitation and GST-pulldown to investigate the molecular machanism of derlin-1 mediated EGFR-TKI resistance in lung cancer cells. We will also use animal model and clinical samples to explore the clinical significance of Derlin-1 in predicting EGFR-TKI sensitivity and patient prognosis.