肺癌EGFR酪氨酸激酶抑制剂(EI)耐药是临床上亟待解决的难题。近期研究发现非小细胞肺癌向小细胞肺癌表型转化是EI耐药的原因之一，然而关于这种表型转化的分子机制至今还不是很清楚。本课题组在前期工作中建立了一种EI诱导的表型转化细胞模型，进一步研究发现以组蛋白甲基转移酶EHMT2为代表的表观调控酶在转化过程中发挥重要作用，基因沉默或化学干预EHMT2能够逆转表型转化，增敏EI作用，提示EHMT2在表型转化及其所介导的EI耐药过程中的关键作用。然而，对于EHMT2在EI诱导的表型转化中的确切角色，以及靶向EHMT2的潜在治疗价值还待进一步阐明。为此，本课题拟采用多种分子生物学方法：1）深入探索EHMT2在表型转化及其所介导的肺癌EI耐药过程中的作用，以期全面认识肺癌EI耐药形成机制；2）进一步探究靶向干预EHMT2对表型转化及其介导的EI耐药的逆转作用，从而为此类耐药患者的治疗提供新路径。

The epithelial growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a key barrier to the treatment of non-small-cell lung cancer (NSCLC). Recently, several studies reported that the phenotype transformation from NSCLC to small-cell lung cancer (SCLC) might be contribute to EGFR-TKI resistance, but the precise molecular mechanisms underlying this transformation remain largely unknown. In our precious study, we firstly established an EGFR-TKI induced cell-based transformation model and evaluated the difference at mRNA profile between transformed cells and parental cells. Our data showed that epigenetic regulation related enzymes, especially euchromatic histone-lysine N-methyltransferase 2 (EHMT2), displayed an obvious aberration. Further study indicated that silencing EHMT2 by siRNA, or suppressing EHMT2 by specific inhibitor, could reverse the phenotype transformation from NSCLC to SCLC, and enhance the sensitivity of transformed cells to EGFR-TKI, suggesting the important role of EHMT2 in the EGFR-TKI induced phenotype transformation and its mediated drug resistance. However, the precise role of EHMT2 and its therapeutic potential in EGFR-TKI elicited phenotype transformation and its mediated drug resistance need to be further investigated. Therefore, we plan to: 1) explore the role of EHMT2 in EGFR-TKI induced phenotype transformation and its mediated drug resistance, which will be benefit to comprehensively understand the development and progression of NSCLC EGFR-TKI resistance；2）investigate the therapeutic value of targeting EHMT2 by small molecular inhibitor in phenotype transformation and its mediated drug resistance, which will provide a novel path for reversing phenotype transformation mediated EGFR-resistance.