基于并发共激活效应的非小细胞肺癌诱发EGFR成瘾机制研究

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have gained approval for use in patients with non-small-cell lung cancer (NSCLC) due to its addiction to EGFR for survival. However, targeting therapy based on EGFR could not reduce mortality in patients with advanced lung cancer because of a secondary resistance mutation. We suggest that driving EGFR mutations repeatedly in lung cancer cells to meet addiction needs may be the root cause of poor treatment efficacy of EGFR-targeted drug. It is therefore important to study the mechanisms of NSCLC-evoked EGFR addiction in order to develop truly effective drugs. To drive EGFR over-expression in NSCLC is another form of oncogene addiction to EGFR. It’s reasonable to take the addiction form based on driving EGFR over-expression in NSCLC as the model to study the initiative mutations which driven EGFR mutation by screening the involved mutation pathway inhibitors after analyzing the data released from Tumor Sequencing Project. The validation of results could be achieved by experiments carried our in EGFR-overexpression addiction and EGFR-mutation addiction two models, after this project is completed, the exact pathogenesis of NSCLC will be supplied, which could provide a theoretical basis for new drug design.

非小细胞肺癌对EGFR的“成瘾性”，是该类肺癌靶向治疗药物发挥作用的原理。但临床应用发现，以EGFR为靶点的靶向治疗药物并不能降低晚期肺癌患者的致死率，其原因是EGFR发生“再次突变”所致。本课题提出，肺癌细胞驱动EGFR反复突变以满足其成瘾性需要，是EGFR靶向性治疗药物疗效欠佳的原因。因此，明确非小细胞肺癌诱发EGFR成瘾的作用机制，可能是研究真正有效药物的关键。本课题以非小细胞肺癌驱动EGFR高表达这种“成瘾”模式为模型，结合肿瘤测序计划公布的相关数据，以调控EGFR表达的关键转录因子为媒介，筛选涉及变异通路抑制剂，并以EGFR“高表达成瘾”模型和EGFR“突变成瘾”模型进行验证，找到与EGFR“被动突变”并发共激活的“主动突变”，明确非小细胞肺癌的发病机制，为新型药物的设计提供理论依据。

非小细胞肺癌对EGFR的“成瘾性”，是该类肺癌靶向治疗药物发挥作用的原理。但临床应用发现，以EGFR为靶点的靶向治疗药物并不能降低晚期肺癌患者的致死率，其原因是EGFR发生“再次突变”所致。为了明确非小细胞肺癌诱发EGFR突变的作用机制，本项目成功筛选出EGFR高表达模式细胞株，系统研究了调控EGFR表达的转录因子。结合肿瘤测序计划公布的相关数据，筛选涉及变异通路抑制剂，确定了细胞周期变异通路及p53失活对非小细胞肺癌诱发EGFR成瘾的重要性。通过系统研究细胞周期变异通路及p53失活在非小细胞肺癌发生、发展中的作用，初步确定了其作为肺癌治疗靶点的可行性，为新型药物的设计提供理论依据。本项目共发表SCI二区论文3篇，获得中国发明专利授权2项，培养硕士毕业生3人。