NF1基因异常在肺腺癌发生中作用与机制研究

随着对肺癌发生分子机制深入研究和靶向药物的开发，肺癌的治疗已进入了以分子分型为基础的个体化靶向治疗时代。NF1是MAPK信号通路中最重要的关键分子，NF1基因的失活可以导致RAS-RAF信号通路的过度激活，从而可能与多种肿瘤的发生有关。近期肺腺癌中研究发现NF1突变与已知驱动基因突变不共存，提示其可能为肺癌中一个新的驱动突变。但其是否具有驱动肿瘤发生功能及具体致癌机制目前未知。本研究首先通过大规模肺腺癌样本分析NF1基因突变谱及NF1突变阳性肺腺癌患者临床病理特征；接着通过CRISPR/Cas9基因编辑技术分析NF1突变蛋白在肺腺癌发生中作用与机制，并筛选潜在有效的靶向药物；最后通过显微切割肺腺癌各个亚型验证NF1基因突变或失活是否参与了腺癌亚型的形成。本研究可为肺腺癌的靶向治疗增加一种新的靶点，推动针对NF1的靶向治疗临床试验的开展。

With deep exploration into the mechanism of driver mutations and development of small agents, molecular subtype-based individualized target therapy has become the leading treatment consideration for lung cancer. Neurofibromin-1(NF1) , a key regulator of MAPK pathway, encodes a Ras-GTPase activating protein(RasGAP). Loss-of-function mutation in NF1, triggers the aberrant activation of the Ras pathway, which underlines formation of multiple tumors. First, we intend to analyze the clinicopathologic features of NF1-mutated patients with lung adenocarcinomas by large scale gene sequencing. Second, NF1-mutated Cell lines and mouse models are constructed by using CRISPR/Cas9 and used to explore the roles in the development of lung adenocarcinoma. Third, by using microdisection and sequencing, the role of NF1 in the formation of subtype of adenocarcinoma will be investigated. Generally, this project will define new targetable oncogenic mutations, and facilitate the conduct of NF1-related clinical trials。