Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells

被引:67
作者
Jiang, Xiao-Ming [1 ]
Xu, Yu-Lian [1 ]
Huang, Mu-Yang [1 ]
Zhang, Le-Le [1 ]
Su, Min-Xia [1 ]
Chen, Xiuping [1 ]
Lu, Jin-Jian [1 ]
机构
[1] Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Macau, Peoples R China
关键词
non-small cell lung cancer; EGFR; osimertinib; PD-L1; ubiquitin-proteasome system; MG-132; bortezomib; GSK3; beta; LiCl; PD-L1; EXPRESSION; REGULATES PD-L1; ASSOCIATION; PATHWAY; PEMBROLIZUMAB; THERAPY; SYSTEM; NSCLC;
D O I
10.1038/aps.2017.123
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In NSCLC patients, an EGFR mutation is likely to be correlated with high levels of expression of programmed death ligand-1 (PD-L1). Here, we showed that osimertinib decreased PD-L1 expression in human EGFR mutant NSCLC cells in vitro. Osimertinib (125 nmol/L) markedly suppressed PD-L1 mRNA expression in both NCI-H1975 and HCC827 cells. Pretreatment with the N-linked glycosylation inhibitor tunicamycin, osimertinib clearly decreased the production of new PD-L1 protein probably due to a reduction in mRNA. After blocking transcription and translation processes with actinomycin D and cycloheximide, respectively, osimertinib continued to reduce the expression of PD-L1, demonstrating that osimertinib might degrade PD-L1 at the post-translational level, which was confirmed by a cycloheximide chase assay, revealing that osimertinib (125 nmol/L) decreased the half-life of PD-L1 from approximately 17.8 h and 13.8 h to 8.6 h and 4.6 h, respectively, in NCI-H1975 and HCC827 cells. Pretreatment with the proteasome inhibitors (MG-132 or bortezomib) blocked the osimertinibinduced degradation of PD-L1, but an inhibitor of autophagy (chloroquine) did not. In addition, inhibition of GSK3 beta by LiCl prevented osimertinib-induced PD-L1 degradation. The results demonstrate that osimertinib reduces PD-L1 mRNA expression and induces its protein degradation, suggesting that osimertinib may reactivate the immune activity of T cells in the tumor microenvironment in EGFR-mutated NSCLC patients.
引用
收藏
页码:1512 / 1520
页数:9
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