c-Met扩增是非小细胞肺癌gefitinib继发耐药的主要机制之一。转录因子KLF4参与多种肿瘤的发生发展，但在肺癌发病中的生物学功能还不清楚。课题组前期研究发现，在c-Met扩增介导的非小细胞性肺癌gefitinib耐药细胞内，KLF4异常高表达。基因沉默KLF4表达明显恢复了耐药细胞对gefitinib的敏感性。进一步研究发现，KLF4参与调控gefitinib耐药细胞内Akt信号通路活化，在耐药细胞内c-Met蛋白存在明显的胞核移位。因此，课题组推测，KLF4通过与c-Met蛋白在胞核内相互作用，共同调节受体酪氨酸激酶信号通路中关键接头蛋白的表达，促进Akt的活化，最终导致肺癌细胞耐药。通过本项目的研究，将从一个新的研究方向阐明c-Met在gefitinib继发耐药中的机制，为肺癌靶向治疗提供新思路，为靶向受体酪氨酸激酶和转录因子抑制剂的联用提供重要的临床和应用的理论依据。

c-Met amplification is one of the major mechanisms which involved in gefitinib acquired resistance in non-small cell lung cancer. The transcription factor KLF4 is always dysregulated in the occurrence and development of malignant tumor, however, its contributions to lung tumorigenesis are unclear. Our previous study revealed that KLF4 was highly expressed in c-Met amplification mediated gefitinib acquired resistance non-small cell lung cancer cells. Knock down of KLF4 expression substantially promoted the sensitivity to gefitinib in resistant cell. Additionally, we found that KLF4 is involved in activation of Akt signaling pathway in resistant cell. Meanwhile, we demonstrated that c-Met is localized in nucleus in this resistant cell. Thus, we hypothesis that KLF4 and c-Met may bind with each other in nucleus and regulate the expression of key adaptor proteins which involved in receptor tyrosine kinases signaling pathways. This regulation will finally induce Akt activation and lead to gefitinib resistance in non-small cell lung cancer.Our study will provide new ideas for gefitinib targeted therapy. Besides, it will have an important clinical significance and application prospects for the development and combination of inhibitors targeting receptor tyrosine kinases and transcription factors.