Evidence map›Paper›PMID 41068729›Full record

ArticleJournal of biomedical science2025

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

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 and 2 more

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Article in Journal of biomedical science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

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3 · Its place in the literature

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1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

12 authors.

Chia-Chi Hsu *Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Derek De-Rui Huang *Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Wei-Hsun HsuDepartment of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Min-Shu HsiehDepartment of Pathology and Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
Fang-Yu LinGraduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.
Pei-Chen TaiGraduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.
Shih-Yun ChouDepartment of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Hsin-Hui TsaiGraduate Institute of Oncology, National Taiwan University, Taipei, Taiwan.
Chen-Yuan TsengInstitute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
Bin-Chi LiaoDepartment of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
Jin-Yuan ShihDepartment of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
James Chih-Hsin YangDepartment of Oncology, National Taiwan University Hospital, Taipei, Taiwan. chihyang@ntu.edu.tw.

Funding

Ministry of Education 112L901403National Science and Technology Council 111-2811-B-002-058National Taiwan University Cancer Center NTUCCS-113-05
6 · The paper itself

Abstract

backgroundProgrammed 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.

methodsThe 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.

resultsIn 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.

conclusionIn EGFR-mutant NSCLC, PD-L1 regulates c-MET phosphorylation and promotes MET amplification, contributing to osimertinib resistance.

Indexed as

AcrylamidesAniline CompoundsB7-H1 AntigenCarcinoma, Non-Small-Cell LungDrug Resistance, NeoplasmLung NeoplasmsProto-Oncogene Proteins c-metAnimalsCell Line, TumorErbB ReceptorsHumansIndolesMiceMutationPhosphorylationPyrimidinesAcrylamidesAniline CompoundsB7-H1 AntigenCD274 protein, humanEGFR protein, humanErbB ReceptorsIndolesMET protein, humanosimertinibProto-Oncogene Proteins c-metPyrimidinesEpidermal growth factor receptor tyrosine kinase inhibitorMET amplificationNon-small cell lung cancerOsimertinib resistanceProgrammed death-ligand 1

Identifiers

PMID41068729
PMCPMC12509346

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