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Osimertinib (AZD9291) decreases programmed death ligand-1 in EGFR-mutated non-small cell lung cancer cells
- Source :
- Acta Pharmacologica Sinica. 38:1512-1520
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
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 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.
- Subjects :
- 0301 basic medicine
Proteasome Endopeptidase Complex
Lung Neoplasms
Time Factors
medicine.drug_class
Down-Regulation
Antineoplastic Agents
Cycloheximide
Protein degradation
B7-H1 Antigen
Piperazines
Tyrosine-kinase inhibitor
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Tumor Microenvironment
medicine
Humans
Pharmacology (medical)
Osimertinib
RNA, Messenger
Epidermal growth factor receptor
Phosphorylation
Protein Kinase Inhibitors
Pharmacology
Acrylamides
Aniline Compounds
Glycogen Synthase Kinase 3 beta
Dose-Response Relationship, Drug
biology
Bortezomib
General Medicine
Tunicamycin
Molecular biology
ErbB Receptors
Gene Expression Regulation, Neoplastic
030104 developmental biology
chemistry
Cell culture
030220 oncology & carcinogenesis
Mutation
Proteolysis
biology.protein
Original Article
medicine.drug
Subjects
Details
- ISSN :
- 17457254 and 16714083
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- Acta Pharmacologica Sinica
- Accession number :
- edsair.doi.dedup.....98c004637ca07cb602840bd7a883964e