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Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells
Jiang, Xiao-Ming; Xu, Yu-Lian; Huang, Mu-Yang; Zhang, Le-Le; Su, Min-Xia; Chen, Xiuping; Lu, Jin-Jian
2017-11
Source PublicationACTA PHARMACOLOGICA SINICA
ISSN1671-4083
Volume38Issue:11Pages:1512-1520
Abstract

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.

KeywordNon-small Cell Lung Cancer Egfr Osimertinib Pd-l1 Ubiquitin-proteasome System Mg-132 Bortezomib Gsk3 Beta Licl
DOI10.1038/aps.2017.123
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry ; Pharmacology & Pharmacy
WOS SubjectChemistry, Multidisciplinary ; Pharmacology & Pharmacy
WOS IDWOS:000414248600009
PublisherACTA PHARMACOLOGICA SINICA
The Source to ArticleWOS
Fulltext Access
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Cited Times [WOS]:11   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
AffiliationState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Jiang, Xiao-Ming,Xu, Yu-Lian,Huang, Mu-Yang,et al. Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2017,38(11):1512-1520.
APA Jiang, Xiao-Ming.,Xu, Yu-Lian.,Huang, Mu-Yang.,Zhang, Le-Le.,Su, Min-Xia.,...&Lu, Jin-Jian.(2017).Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells.ACTA PHARMACOLOGICA SINICA,38(11),1512-1520.
MLA Jiang, Xiao-Ming,et al."Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells".ACTA PHARMACOLOGICA SINICA 38.11(2017):1512-1520.
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