Journal of biomedical science · 2025
PD-L1 regulates c-MET phosphorylation and contributes to MET-dependent resistance to osimertinib in EGFR-mutant NSCLC.
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Hsu Chia-Chi, Huang Derek De-Rui, Hsu Wei-Hsun, Hsieh Min-Shu, Lin Fang-Yu, Tai Pei-Chen, Chou Shih-Yun, Tsai Hsin-Hui, Tseng Chen-Yuan, Liao Bin-Chi, Shih Jin-Yuan, Yang James Chih-Hsin
Аннотация
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.
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.