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YTHDC2 inhibits the resistance of lung cancer to EGFR-TKI through cuproptosis

Oncogene volume 45, pages 431–445 (2026)Cite this article

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Abstract

While third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib, have significantly improved patient survival in non-small cell lung cancer (NSCLC), acquired resistance remains a major clinical challenge, and its underlying mechanisms are incompletely understood. In this study, we demonstrate that YTHDC2 expression is significantly downregulated in osimertinib-resistant patient-derived xenograft (PDX) tissues and lung cancer cell lines compared to their osimertinib-sensitive counterparts. Further investigation revealed that YTHDC2 overcomes osimertinib resistance in lung cancer cells by promoting cuproptosis. Mechanistically, YTHDC2 binds to m6A-modified sites (specifically at nucleotides A1223 and A2824) within the mRNA of the copper transporter SLC31A1 in an m6A-dependent manner. This interaction enhances SLC31A1 mRNA stability and protein expression, thereby increasing intracellular copper transport and inducing cuproptosis in tumor cells. Additionally, we found that the copper ionophore disulfiram (DSF) overcame osimertinib resistance by augmenting YTHDC2 expression. Collectively, our findings elucidate a novel YTHDC2-SLC31A1-cuproptosis axis as a key mechanism underlying EGFR-TKI resistance and propose new therapeutic strategies for its reversal.

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Fig. 1: YTHDC2 is a critical regulator in EGFR-TKI osimertinib resistance.
Fig. 2: YTHDC2 inhibits osimertinib resistance.
Fig. 3: YTHDC2 regulates osimertinib resistance by cuproptosis.
Fig. 4: Copper transporter SLC31A1 is a target of YTHDC2.
Fig. 5: YTHDC2 regulates cuproptosis by targeting SLC31A1.
Fig. 6: YTHDC2 binds to m6A-modified SLC31A1 mRNA and sustains SLC31A1 mRNA stability.
Fig. 7: DSF regulates cuproptosis by targeting YTHDC2 to improve osimertinib resistance.
Fig. 8: Schematic illustration of the mechanism by which YTHDC2 targets SLC31A1 in an m6A-dependent manner mediated cuproptosis to regulate EGFR-TKI resistance.

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All data are included in the manuscript or available from corresponding authors upon reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82472771, 82273139, 82272679, 82303043, 32470821); Shanghai Eastern Talent Plan - Youth Project (QNWS2024061); Shanghai Municipal Health Commission, Clinical Research Special Project for Young Scholars (20234Y0019).

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Author notes

  1. These authors contributed equally: Jizhuang Luo, Xin Xu, Yaohui Chen.

Authors and Affiliations

  1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jizhuang Luo & Tianxiang Chen

  2. Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Xin Xu, Yiwen Huang, Yiman Huang & Yajuan Zhang

  3. Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yaohui Chen & Lifang Ma

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  1. Jizhuang Luo
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Contributions

Jizhuang Luo: Writing – original draft, Methodology, Investigation, Formal analysis, Funding acquisition. Xin Xu: Writing – original draft, Investigation, Formal analysis, Data curation, Funding acquisition. Yaohui Chen: Formal analysis, Data curation. Yiwen Huang: Formal analysis, Data curation. Yiman Huang: Formal analysis. Yajuan Zhang: Writing – review and editing, Conceptualization, Funding acquisition. Lifang Ma: Writing – review and editing, Methodology, Supervision, Conceptualization, Funding acquisition. Tianxiang Chen: Supervision, Conceptualization, Project administration, Funding acquisition. All authors approved the paper.

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Correspondence to Yajuan Zhang, Lifang Ma or Tianxiang Chen.

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Luo, J., Xu, X., Chen, Y. et al. YTHDC2 inhibits the resistance of lung cancer to EGFR-TKI through cuproptosis. Oncogene 45, 431–445 (2026). https://doi.org/10.1038/s41388-025-03660-1

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