临床常使用酪氨酸激酶抑制剂（TKI）治疗具有表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC），但仍有相当部分患者疗效不佳。研究表明EGFR通路与表观遗传调控关系密切。申请人发现约80%EGFR突变的NSCLC临床组织中表观遗传修饰酶-组蛋白去甲基化酶UTX表达升高；在NSCLC细胞中UTX与EGFR存在相互正反馈调控关系，敲低UTX或利用UTX抑制剂可显著增强TKI对EGFR突变NSCLC细胞的杀伤效果。申请人据此提出“UTX是NSCLC治疗潜在靶点，UTX与EGFR之间存在正反馈调控环路，抑制UTX能通过抑制EGFR通路协同提高TKI的抗NSCLC效果”研究假说。本项目拟从分子和细胞水平探索UTX在NSCLC中对EGFR的表观遗传调控作用；利用动物模型研究UTX抑制剂联合TKI治疗NSCLC的效果及分子机制；有望为发现抗NSCLC药物新靶点提供理论依据，为临床治疗提供新策略。

Tyrosine kinase inhibitors (TKIs) treatments are often selected for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations, however, some patients are not sensitive to TKI. Studies have shown that EGFR pathway is closely related to epigenetic regulation. We have found that histone demethylase UTX is elevated in about 80% of EGFR mutant NSCLC. In NSCLC cell lines, UTX and EGFR was positively correlated with each other，and UTX knockdown or UTX inhibitor could significantly enhance the TKI killing effects on EGFR mutant NSCLC cells. According to these results, we propose that "UTX is a potential target for NSCLC treatment, and there is a positive feedback loop between UTX and EGFR. Inhibition of UTX will improve the anti-NSCLC effects of TKI by blocking EGFR pathway". This study will explore the role of UTX in the epigenetic regulation on EGFR in NSCLC at molecular and cellular levels. We will also evaluate the combined effect of UTX inhibitor and TKI on NSCLC treatment in animal model. This study will discover a theoretical basis for new anti-NSCLC drug targets and provide new strategies for NSCLC clinical treatment.