使用表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKIs)治疗能够给EGFR突变的非小细胞肺癌(NSCLC)患者带来显著的益处。然而，大部分患者在治疗后最终会产生获得性耐药性。本研究调查了粘液糖蛋白17(MUC17)对EGFR-TKIs获得性耐药细胞的表观遗传效应。我们发现，GR/OR(吉非替尼/奥西替尼耐药)细胞在全基因组DNA高甲基化中起到了主要作用，主要是与多种致癌通路相关的5'UTR，其中GR/OR细胞通过剂量和时间依赖性的下调MUC17表达来发挥促癌作用。吉非替尼/奥西替尼获得性耐药通过促进DNMT1/UHRF1复合体依赖的启动子甲基化降调MUC17，从而激活NF-κB活性。MUC17通过促进MZF1表达增加IκB-α的产生并抑制NF-κB活性。体内结果也显示，DNMT1抑制剂(5-Aza)与吉非替尼/奥西替尼联合使用可恢复OR/GR细胞的敏感性。吉非替尼/奥西替尼的获得性耐药性促进了UHRF1/DNMT1复合物抑制MUC17的表达。GR/OR细胞中的MUC17可能作为一种表观遗传传感器，用于监测对EGFR-TKIs的耐受性。 ©作者。

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has brought significant benefits to non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most patients eventually develop acquired resistance after treatment. This study investigated the epigenetic effects of mucin 17 (MUC17) in acquired drug-resistant cells of EGFR-TKIs. We found that GR/OR (gefitinib/osimertinib-resistance) cells enhance genome-wide DNA hypermethylation, mainly in 5-UTR associated with multiple oncogenic pathways, in which GR/OR cells exerted a pro-oncogenic effect by downregulating mucin 17 (MUC17) expression in a dose- and time-dependent manner. Gefitinib/osimertinib acquired resistance mediated down-regulation of MUC17 by promoting DNMT1/UHRF1 complex-dependent promoter methylation, thereby activating NF-κB activity. MUC17 increased the generation of IκB-α and inhibit NF-κB activity by promoting the expression of MZF1. In vivo results also showed that DNMT1 inhibitor (5-Aza) in combination with gefitinib/osimertinib restored sensitivity to OR/GR cells. Acquired drug resistance of gefitinib/osimertinib promoted UHRF1/DNMT1 complex to inhibit the expression of MUC17. MUC17 in GR/OR cells may act as an epigenetic sensor for biomonitoring the resistance to EGFR-TKIs.© The author(s).