WCLC 2025 - Posters & ePosters-EP.03.04 PD-L1-Regulated c-Met Phosphorylation Contributes to MET Amplification in EGFR Mutation NSCLC

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This study investigates the regulatory role of PD-L1 on c-MET phosphorylation in EGFR-mutant (EGFR⁺) non-small cell lung cancer (NSCLC). The authors demonstrate that PD-L1 expression directly influences c-MET activation, which is a critical pathway implicated in cancer progression and resistance mechanisms.<br /><br />Key findings include that PD-L1 knock-out or knock-down reduces c-MET phosphorylation levels, indicating PD-L1 as a positive regulator of c-MET activity in EGFR⁺ NSCLC cells. Overexpression of PD-L1 upregulates c-MET phosphorylation by inhibiting protein tyrosine phosphatases (PTPs), enzymes responsible for dephosphorylating c-MET. This was supported by assays showing reduced PTP activity with PD-L1 overexpression and increased c-MET phosphorylation upon inhibition of PTPs.<br /><br />Figures from the study reveal that stable PD-L1 overexpression in NCI-H1975 cells increases c-MET phosphorylation, particularly under varying serum concentrations and IFN-γ stimulation. Conversely, PD-L1 knock-out cells showed diminished c-MET phosphorylation, which could be rescued by PTP inhibitors like Na3VO4 and BMOV, confirming PTP inhibition as a mechanism for PD-L1-mediated c-MET activation.<br /><br />Clinically significant is the observation that EGFR-mutant NSCLC cells exhibiting c-MET phosphorylation are predisposed to MET gene amplification. This amplification serves as a bypass resistance mechanism against osimertinib, a third-generation EGFR tyrosine kinase inhibitor used in therapy. Therefore, PD-L1-driven c-MET activation may contribute to therapeutic resistance.<br /><br />In conclusion, PD-L1 acts as a regulator of c-MET phosphorylation in EGFR-mutant NSCLC by suppressing PTPs, promoting c-MET activation and potentially leading to resistance through MET amplification under osimertinib treatment. This insight suggests that targeting PD-L1 or related pathways could help overcome resistance in EGFR-mutant NSCLC. The study was supported by grants from the National Science and Technology Council, National Taiwan University Cancer Center, and the Ministry of Education.

Asset Subtitle

Derek De-Rui Huang

Meta Tag

Speaker Derek De-Rui Huang

Topic Tumor Biology – Translational Biology

Keywords

PD-L1

c-MET phosphorylation

EGFR-mutant NSCLC

non-small cell lung cancer

protein tyrosine phosphatases

PTP inhibition

MET gene amplification

osimertinib resistance

cancer progression

therapeutic resistance