VEGFR2/KDR基因扩增在非小细胞肺癌化疗抵抗中的作用及机制研究

VEGF receptor-2 (VEGFR-2 or kinase insert domain receptor, KDR) is the predominant mediator of VEGF-stimulated endothelial cell functions, including cell migration, proliferation, survival, and enhancement of vascular permeability. High expression of VEGFR-2 is detected in some somatic tumors including lung cancer although the molecular abnormality of KDR gene in tumor cells is rarely reported. Our previous study represents the first report in lung cancer showing a high frequency of KDR copy number gain (CNG) (32%) in both major histology types of NSCLC, adenocarcinoma, and squamous cell carcinoma. Notably, KDR CNG predicted worse OS in patients who received platinum adjuvant therapy but not in untreated patients. However, the mechanism of chemoresistence related with KDR CNG is unknown. .Objective of the project is to characterize the molecular mechanisms associated with KDR CNG in adjuvant therapy in NSCLC, particularly the potential role of factors in PLC-γ/MAPK/ERK、PI3K/Akt pathway. The relations between KDR CNG with the factors in those pathways will be investigated by in vivo and in vitro sensitivity to cisplatin, paclitaxel and VEGFR targeted medicine Vandetanib in lung cancer. It is also detected in the resected tumor tissues of lung cancer patients in China. Sensitivity to therapy in siKDR transfected cells will be compared with control siRNA-transfected or untransfected cells in small interfering RNA (siRNA) examination. The result is helpful for identifying useful biomarkers to select patients that may benefit from adjuvant chemotherapy and VEGFR-2 blockade in NSCLC.

血管内皮生长因子受体2（VEGFR2/KDR）在促进肿瘤血管生成、调节细胞增殖及分化等方面发挥着重要作用。肺癌细胞VEGFR2蛋白常出现异常表达，但其编码基因KDR的遗传学改变及临床意义的报道较少。最新研究提示32%非小细胞肺癌中出现KDR基因的异常扩增，这类患者在术后辅助性化疗中存在明显的治疗抵抗，生存期短，但其分子机制不清。为阐明KDR基因扩增在肺癌辅助性治疗抵抗中的作用机制，本项目拟以KDR介导的PLC-γ/MAPK/ERK、PI3K/Akt信号通路为中心，通过肺癌细胞、移植瘤模型及人肺癌标本，采用紫杉醇与顺铂抑制、靶向药物Vandetanib阻断、RNA干扰基因沉默及基因过表达技术等研究化疗药物耐受、VEGFR2/KDR信号通路和KDR基因拷贝数量获得（CNG）三者间的关系，并评价KDR基因拷贝数作为抗血管生成靶向治疗效果预测性指标的价值，为肺癌的个性化治疗提供新思路和理论依据。

血管内皮生长因子受体2（VEGFR2/KDR）在促进肿瘤血管生成、调节细胞增殖及分化等方面发挥着重要作用。肺癌细胞VEGFR2蛋白常出现异常表达，但其编码基因KDR的遗传学改变及临床意义的报道较少。最新研究提示32%非小细胞肺癌中出现KDR基因的异常扩增，这类患者在术后辅助性化疗中存在明显的治疗抵抗，生存期短，但其分子机制不清。为阐明KDR基因扩增在肺癌辅助性治疗抵抗中的作用机制，本课题用RNA干扰基因沉默及基因过表达技术等研究VEGFR2/KDR信号通路和KDR基因拷贝数量之间的关系，并评价KDR基因拷贝数作为抗血管生成靶向治疗效果预测性指标的价值，为肺癌的个性化治疗提供新思路和理论依据。