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

作　　者：Xiao-Ming JIANG Yu-Lian XU Mu-Yang HUANG Le-Le ZHANG Min-Xia SU Xiuping CHEN Jin-Jian LU 

机构地区：[1]State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macao, Macao, China

出　　处：《Acta Pharmacologica Sinica》2017年第11期1512-1520,共9页中国药理学报（英文版）

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 osimertinib- induced degradation of PD-L1, but an inhibitor of autophagy （chloroquine） did not. In addition, inhibition of GSK3β 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.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 osimertinib- induced degradation of PD-L1, but an inhibitor of autophagy （chloroquine） did not. In addition, inhibition of GSK3β 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.

关 键 词：non-small cell lung cancer EGFR osimertinib PD-L1 ubiquitin-proteasome system MG-132 BORTEZOMIB GSK3p LICL 

分 类 号：R[医药卫生]