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Background <p>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 (<i>EGFR</i>)-mutant NSCLC remains unclear. This study aims to investigate the impact of PD-L1 on the signaling pathways in <i>EGFR</i>-mutant NSCLC.</p> Methods <p>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.</p> Results <p>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, <i>MET</i> 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.</p> Conclusion <p>In <i>EGFR</i>-mutant NSCLC, PD-L1 regulates c-MET phosphorylation and promotes <i>MET</i> amplification, contributing to osimertinib resistance.</p>

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PD-L1 regulates c-MET phosphorylation and contributes to MET-dependent resistance to osimertinib in EGFR-mutant NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月9日

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  • Chia-Chi Hsu,
  • Derek De-Rui Huang,
  • Wei-Hsun Hsu,
  • Min-Shu Hsieh,
  • Fang-Yu Lin,
  • Pei-Chen Tai,
  • Shih-Yun Chou,
  • Hsin-Hui Tsai,
  • Chen-Yuan Tseng,
  • Bin-Chi Liao,
  • Jin-Yuan Shih,
  • James Chih-Hsin Yang

摘要

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.