N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism
Abstract As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary an...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-06-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07764-0 |
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| Summary: | Abstract As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC. |
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| ISSN: | 2041-4889 |