An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling

Eur J Cancer. 2017 Nov;85:95-105. doi: 10.1016/j.ejca.2017.07.025. Epub 2017 Sep 9.

Abstract

High programmed cell death 1 ligand 1 (PD-L1) expression in tumour tissues was associated with poor outcomes in non-small cell lung cancer (NSCLC) due to evasion of tumour immune surveillance. However, the role of PD-L1 in tumour invasion and resistance to tyrosine kinase inhibitor (TKI) treatments is not fully understood. Here, we provide evidence to support the involvement of PD-L1 expression in the invasiveness and TKI resistance in NSCLC cells by increased Bcl-2-associated athanogene-1 (BAG-1) expression. The upregulation of BAG-1 transcription by PD-L1 was verified by constructing the BAG-1 promoters using the polymerase chain reaction (PCR) and deletion mutations for luciferase reporter assays. The results indicated that C/EBPβ phosphorylation by extracellular signal-regulated kinase (ERK) signalling was responsible for PD-L1-mediated BAG-1 transcription. Mechanistically, the PD-L1-induced BAG-1 expression reciprocally increased PD-L1 expression due to persistent activation of ERK signalling, and it consequently conferred TKI resistance in NSCLC cells. The mechanistic action of this cell model was further confirmed by an animal model, affirming that PD-L1 conferred tumour invasiveness and TKI resistance via persistent activation of ERK signalling by the PD-L1/BAG-1 axis. We therefore suggest a combination of an ERK inhibitor with a TKI as a potential strategy for conquering PD-L1-mediated tumour invasion and TKI resistance in NSCLC patients whose tumours harbour high PD-L1/high BAG-1 expression.

Keywords: BAG-1; BIM; EGFR; NSCLC; PD-L1.

MeSH terms

  • A549 Cells
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Bcl-2-Like Protein 11 / metabolism
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Movement / drug effects
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Disease-Free Survival
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Gefitinib
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Stability
  • Quinazolines / pharmacology*
  • RNA Interference
  • Signal Transduction / drug effects*
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • BCL2-associated athanogene 1 protein
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • CCAAT-Enhancer-Binding Protein-beta
  • CD274 protein, human
  • CEBPB protein, human
  • DNA-Binding Proteins
  • Protein Kinase Inhibitors
  • Quinazolines
  • Transcription Factors
  • EGFR protein, human
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • Gefitinib