Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer.
Role of PARP1-mediated autophagy in EGFR-TKI resistance in non-small cell lung cancer.
复制标题
DOI：
10.1038/s41598-020-77908-z
复制
发表时间：
2020-12-01
影响因子：
4.6
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Zhang Z;Lian X;Xie W;Quan J;Liao M;Wu Y;Yang ZZ;Wang G
对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）的耐药已成为晚期肺癌的主要临床挑战。本研究旨在探讨PARP 1介导的自噬在TKI治疗进展中的作用。通过CCK-8测定、克隆形成测定、免疫荧光和蛋白质印迹法，在单独或联合使用埃克替尼（Ico）、雷帕霉素和AZD 2281（奥拉帕尼）处理的HCC-827、H1975和H1299细胞中，对PARP 1介导的自噬进行了体外评价。我们的结果和GEO数据集分析证实，PARP 1在TKI敏感细胞中的表达水平低于TKI耐药细胞。PARP 1低表达和p62高表达与TKI治疗后NSCLC患者的良好结局相关。AZD 2281和溶酶体抑制剂通过降低细胞中的PARP 1和LC 3逆转对Ico的抗性，但mTOR抑制剂没有降低Ico抗性。AZD 2281和Ico联合使用通过减少体内PARP 1表达和自噬而显着增强抗肿瘤作用。在HCC-827 IR、H1975和H1299细胞中，PARP 1表达的敲低通过mTOR/Akt/自噬途径逆转了对TKI的耐药性。PARP 1介导的自噬是NSCLC细胞中TKI耐药的关键途径，参与TKI耐药。奥拉帕尼可能是克服TKI耐药性的一种新方法。
Resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has become the main clinical challenge of advanced lung cancer. This research aimed to explore the role of PARP1-mediated autophagy in the progression of TKI therapy. PARP1-mediated autophagy was evaluated in vitro by CCK-8 assay, clonogenic assay, immunofluorescence, and western blot in the HCC-827, H1975, and H1299 cells treated with icotinib (Ico), rapamycin, and AZD2281 (olaparib) alone or in combination. Our results and GEO dataset analysis confirmed that PARP1 is expressed at lower levels in TKI-sensitive cells than in TKI-resistant cells. Low PARP1 expression and high p62 expression were associated with good outcomes among patients with NSCLC after TKI therapy. AZD2281 and a lysosomal inhibitor reversed resistance to Ico by decreasing PARP1 and LC3 in cells, but an mTOR inhibitor did not decrease Ico resistance. The combination of AZD2281 and Ico exerted a markedly enhanced antitumor effect by reducing PARP1 expression and autophagy in vivo. Knockdown of PARP1 expression reversed the resistance to TKI by the mTOR/Akt/autophagy pathway in HCC-827IR, H1975, and H1299 cells. PARP1-mediated autophagy is a key pathway for TKI resistance in NSCLC cells that participates in the resistance to TKIs. Olaparib may serve as a novel method to overcome the resistance to TKIs.
登录
查看更多内容
影响因子：
4
作者：
Batson S;Mitchell SA;Windisch R;Damonte E;Munk VC;Reguart N
通讯作者：
Reguart N
影响因子：
3.6
作者：
Fung, Christopher;Chen, Xing;Duvvuri, Umamaheswar
通讯作者：
Duvvuri, Umamaheswar
影响因子：
3.7
作者：
Ethier, Chantal;Tardif, Maxime;Poirier, Guy G.
通讯作者：
Poirier, Guy G.
影响因子：
50.3
作者：
Duran, Angeles;Linares, Juan F.;Moscat, Jorge
通讯作者：
Moscat, Jorge
影响因子：
50.3
作者：
Huang J;Duran A;Reina-Campos M;Valencia T;Castilla EA;Müller TD;Tschöp MH;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT