PD-L1 regulates c-MET phosphorylation and contributes to MET-dependent resistance to osimertinib in EGFR-mutant NSCLC.
Journal
Journal of biomedical science
Journal Volume
32
Journal Issue
1
Start Page
Article number 94
ISSN
1423-0127
Date Issued
2025-10-09
Author(s)
Hsu, Chia-Chi
Hsu, Wei-Hsun
Lin, Fang-Yu
Tai, Pei-Chen
Chou, Shih-Yun
Tsai, Hsin-Hui
Tseng, Chen-Yuan
Abstract
Background: Programmed death-ligand 1 (PD-L1) is a well-recognized predictive biomarker for immunotherapy in non-oncogene-addicted non-small cell lung cancer (NSCLC). However, its role in epidermal growth factor receptor (EGFR)-mutant NSCLC remains unclear. This study aims to investigate the impact of PD-L1 on the signaling pathways in EGFR-mutant NSCLC. Methods: The regulatory role of PD-L1 was investigated through in vitro manipulation of PD-L1 expression across several EGFR-mutant cell lines, followed by analysis via human receptor tyrosine kinase (RTK) array, Western blotting, protein tyrosine phosphatase (PTPs) activity assays, and mRNA expression profiling. In vivo experiments were carried out using xenograft mice implanted with parental, PD-L1 knock-out and PD-L1 overexpression NCI-H1975 cells. Osimertinib was orally administered to the mice until tumor progression to evaluate the impact of PD-L1 on osimertinib resistance. Results: In human RTK array screening, c-MET phosphorylation was found to be increased in EGFR-mutant PD-L1 overexpressing cells. We found that PD-L1 overexpression upregulated c-MET phosphorylation, while PD-L1 knock-out and knock-down resulted in downregulation of c-MET phosphorylation. Furthermore, we showed that PD-L1 upregulates c-MET phosphorylation by suppressing PTP activity and reducing mRNA expression in selected PTPs. In xenograft mice, MET amplification only developed in PD-L1 overexpression, but not in PD-L1 knock-out and parental NCI-H1975 cells, at the time of osimertinib resistance. Conclusion: In EGFR-mutant NSCLC, PD-L1 regulates c-MET phosphorylation and promotes MET amplification, contributing to osimertinib resistance.
Subjects
MET amplification
Epidermal growth factor receptor tyrosine kinase inhibitor
Non-small cell lung cancer
Osimertinib resistance
Programmed death-ligand 1
SDGs
Type
journal article