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

• 来源期刊: 中国药理学报（英文版）
• 关键词: non-small cell lung cancer EGFR osimertinib PD-L1 ubiquitin-proteasome system MG-132 bortezomib GSK3β LiCl
• 年，卷（期）: 2017,（11）
• 页码范围: 1512-1520
• 页数: 9页
• 语种: 英文
• DOI: 10.1038/aps.2017.123

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 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.