EGF/EGFR通过Nrf2通路调控EGFR-TKIs耐药肺癌细胞铁死亡的分子机制研究

EGFR-TKIs耐药是影响肺癌治疗的瓶颈难题。随着新的耐药突变位点的发现，EGFR-TKIs不断换代升级，肺癌的靶向治疗陷入了“西西弗斯”困境。申请人的前期研究发现铁死亡诱导剂可以诱导肺癌细胞铁死亡，杀灭EGFR-TKIs耐药细胞，提示诱导肺癌细胞铁死亡是克服EGFR-TKIs耐药的重要研究方向。本项目拟运用CRISPR/Cas9基因编辑技术，结合转录组、脂质及蛋白质组学研究，探究EGFR通过Nrf2信号通路调控肺癌细胞铁死亡的分子机制；利用肺癌临床标本探明铁死亡相关基因的表达与EGFR-TKIs耐药的关系；通过高通量筛选试验，揭示铁死亡诱导剂与EGFR-TKIs的协同效应。本项目的开展有助于阐明EGF/EGFR通过Nrf2通路调控EGFR-TKIs耐药肺癌细胞铁死亡的分子机制，为患者EGFR-TKIs耐药后的治疗提供新思路，为铁死亡诱导剂的临床应用提供理论基础和关键数据支撑。

EGFR-TKIs resistance is the bottleneck sabotaging a better treatment of lung cancer. With more and more revelations of novel drug-resistant mutation sites, EGFR-TKIs keep upgrading simultaneously, so that current targeted therapy of lung cancer turns out to be a "Sisyphus" dilemma. The applicant's research found that ferroptosis inducers can initiate ferroptosis in lung cancer cells, thereby kill EGFR-TKIs resistant cells, suggesting ferroptosis is an important research path that leads to overcoming EGFR-TKIs resistance. Integrated CRISPR/Cas9 gene-editing technology, transcriptomics, lipid metabolomics, and Proteomic approaches will be used to reveal the molecular mechanism of EGFR modulates ferroptosis in lung cancer cells by the Nrf2 signaling pathway. Clinical specimens of lung cancer will be used to investigate the relationship between the expression of ferroptosis-related genes and EGFR-TKIs resistance; high-throughput screening will be performed to reveal the synergistic effect of ferroptosis inducers and EGFR-TKIs. The development of this project will help clarify the molecular mechanism of EGF/EGFR regulating ferroptosis in EGFR-TKIs resistant lung cancer cells through the Nrf2 pathway, provide new ideas for the treatment of EGFR-TKIs resistance in the clinic, and lay the theoretical foundation and key data support for the clinical application of ferroptosis inducers.