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EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells
BMC Cancer ( IF 3.4 ) Pub Date : 2020-12-04 , DOI: 10.1186/s12885-020-07667-7
Hao Gong , Yongwen Li , Yin Yuan , Weiting Li , Hongbing Zhang , Zihe Zhang , Ruifeng Shi , Minghui Liu , Chao Liu , Chen Chen , Hongyu Liu , Jun Chen

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells. The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting. EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo. These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.

中文翻译:

EZH2抑制剂可逆转原发性EGFR野生型肺癌细胞对吉非替尼的耐药性

肺癌是全球癌症相关死亡的主要原因。非小细胞肺癌(NSCLC)是最常见的肺癌类型。在传统的抗癌治疗中,表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKI)已被证明对EGFR突变患者有益。但是,EGFR野生型NSCLC患者通常对EGFR-TKI没有反应。zeste同源物2(EZH2)的增强子是PRC2复合物中的关键分子,在表观遗传调控中起重要作用,并且在变体肿瘤中过表达。据报道,EZH2抑制剂可使变异的肿瘤细胞对抗癌药敏感。这项研究旨在研究EZH2抑制剂GSK343和DZNep与吉非替尼联合使用是否可以逆转EGFR野生型NSCLC细胞中的EGFR-TKIs耐药性。分析了来自癌症基因组图谱(TCGA)的NSCLC患者[502例肺鳞状细胞癌,包括49例癌旁肺组织和513例肺腺癌(LUAD),包括59例癌旁肺组织]的RNA序列数据。 EZH2表达。通过RT-PCR在来自我们研究所(TJMUGH)的40个NSCLC组织癌样品及其相应的癌旁组织中证实了EZH2表达。siRNA或EZH2抑制剂处理过的A549和H1299细胞通过Western blotting进行细胞活力和凋亡分析以及EGFR途径蛋白表达分析。根据TCGA和TJMUGH的数据,EZH2在人NSCLC组织中上调,并与LUAD患者的预后不良相关。GSK343和DZNep均可通过下调EGFR和AKT的磷酸化并诱导细胞凋亡,使EGFR野生型LUAD细胞(A549和H1299)对吉非替尼敏感,并在体外抑制细胞活力和增殖。与体外和体内单一药物给药相比,EZH2抑制剂(GSK343或DZNep)与吉非替尼的共同给药对肿瘤活性,细胞增殖和细胞迁移具有更强的抑制作用。这些数据表明,EZH2抑制剂与EGFR-TKI的组合可能是治疗不希望接受传统化疗的EGFR野生型NSCLC患者的有效方法。与体外和体内单一药物给药相比,EZH2抑制剂(GSK343或DZNep)与吉非替尼的共同给药对肿瘤活性,细胞增殖和细胞迁移具有更强的抑制作用。这些数据表明,EZH2抑制剂与EGFR-TKI的组合可能是治疗不希望接受传统化疗的EGFR野生型NSCLC患者的有效方法。与体外和体内单一药物给药相比,EZH2抑制剂(GSK343或DZNep)与吉非替尼的共同给药对肿瘤活性,细胞增殖和细胞迁移具有更强的抑制作用。这些数据表明,EZH2抑制剂与EGFR-TKI的组合可能是治疗不希望接受传统化疗的EGFR野生型NSCLC患者的有效方法。
更新日期:2020-12-04
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