项目名称: 双驱动基因驱动肺癌分子靶向治疗的耐药机制
项目编号: No.81472207
项目类型: 面上项目
立项/批准年度: 2015
项目学科: 医药、卫生
项目作者: 杨衿记
作者单位: 广东省人民医院
项目金额: 78万元
中文摘要: 双驱动基因型肺癌近年来备受关注。我们前期研究显示,EGFR突变和ALK融合双驱动基因型肺癌占肺癌的1.3%,其中在EGFR突变型和ALK融合型肺癌中各占3.9%和18.6%;该型肺癌要么对EGFR酪氨酸激酶抑制剂(TKI)有效(有效率80%),要么对ALK TKI有效(有效率50%),提示对其中一种TKI是耐药的,这种耐药性可能与受体相对磷酸化程度有关。但具体的耐药分子机制尚不明确,对双驱动基因型肺癌的精准治疗构成了严峻的挑战。本课题从临床病例构建EGFR突变和ALK融合双驱动基因型肺癌细胞株,按照受体的相对磷酸化程度,给予单药TKI、两种TKI序贯或联用等干预,描绘细胞生长曲线,运用基因测序、FISH和western blotting等方法,检测治疗前后驱动基因、旁路基因和信号通路关键分子及其磷酸化,验证耐药性与基线受体磷酸化水平相关,探讨双驱动基因型肺癌的抗药性策略和精准治疗。
中文关键词: C05_气管;支气管;肺肿瘤;驱动基因;靶向治疗;耐药
英文摘要: Diagnosis of lung cancers with dual oncogenic drivers and their molecularly targeted therapy have been emphasized recently. Our previous study revealed that lung cancer with concurrent EGFR mutation and ALK rearrangement accounts for 1.3% in non-small-cell lung cancer (NSCLC), and 3.9% in EGFR mutant patients and 18.6% in ALK-positive patients. The patients with such EGFR/ALK co-alterations respond to either EGFR tyrosine kinase inhibitor (TKI) (response rate 80%) or ALK TKI (response rate 50%), indicating resistance to either of TKIs, and the resistance might be associated with phosphorylation of EGFR and ALK. However, the molecular mechanism of resistance has not been elucidated, and that could be a challenging problem for the precise treatment of lung cancer with dual oncogenic drivers . The present study sets up cell lines of lung cancer with concurrent EGFR mutation and ALK rearrangement, which are treated with single agent EGFR TKI or ALK TKI, sequential usage of two kinds of TKI and combination of EGFR TKI and ALK TKI respectively, according to the relative phosphorylation of EGFR and ALK. The curves of cell growth are recorded, and oncogenic drivers, bypass genes, key signal molecules and their phosphorylation are also detected before and after treatment for the cell lines using DNA sequencing, FISH and western blotting. Afterthat, the correlationship between the primary resistance to TKI and the level of baseline phosphorylation of receptors will be confirmed. Meanwhile, comparing change of these molecular markers before and after treatment, and analyzing other molecular mechanism of resistance, will lead to better strategies of anti-resistance and precise treatment in lung cancers with dual oncogenic drivers.
英文关键词: trachea;bronchus;lung cancer;oncogenic driver;targeted therapy;resistance