肺癌是对人类健康危害最大的恶性肿瘤之一，其死亡率居恶性肿瘤死亡率之首位。近来， 分子靶向药物表皮生长因子受体酪氨酸酶抑制剂(如吉非替尼或奥西替尼)在肺腺癌的治疗过程中，呈现出起效快、疗效好等特点。但是，在肺腺癌的长期治疗过程中，仍不可避免的出现获得性耐药问题，导致肿瘤复发，已成为影响肺癌治疗的主要瓶颈之一。因此，我们通过运用CRISPR/Cas9筛选技术在全基因组范围内，系统地挖掘了在肺腺癌治疗过程中与EGFR-TKI耐药性相关的基因，其中，对于排名靠前的两个基因YAP1和NEK2进行了耐药功能的初步验证实验，确定了两个基因的确跟奥希替尼耐药相关，因此，接下来通过整合分析ChIP-seq以及RNA-seq和GRO-seq数据，为构建EGFR-TKI耐药基因调控网络，对阐释EGFR-TKI耐药机制及指导临床个体化治疗有着重要的意义。

Lung cancer is one of the most harmful malignant tumors to human health, and its mortality rate ranks first in the death rate of malignant tumor. Recently, molecular targeted drugs Epidermal Growth Factor-Tyrosine Kinase Inhibitor (such as Gefitinib or Osimertinib) are showing a rapid onset, good curative effect in lung adenocarcinoma. However, in the long term treatment of lung adenocarcinoma, the problem of acquired drug resistance is inevitable, resulting in tumor recurrence, which has become one of the main bottlenecks affecting the treatment of lung cancer. Therefore, by utilizing CRISPR/Cas9 screening technology in genome-wide scale, we systematically studied EGFR-TKI drug resistance genes in the treatment of lung adenocarcinoma.For two top ranking genes YAP1 and NEK2, we validated drug resistance function by molecular experiment. The two genes were confirmed to related to Osimertinib resistance. Therefore, by integrating and analyzing ChIP-seq and RNA-seq and GRO-seq data, for the construction of EGFR-TKI resistance gene regulatory network is of great significance to explain the mechanism of resistance to EGFR-TKI and to guide clinical individualized treatment.