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<p>Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a critical challenge in lung adenocarcinoma. Here, we identify ATXN3, a deubiquitinating enzyme, as a driver of Osimertinib resistance and a predictor of poor patient survival. Osimertinib treatment dynamically upregulates ATXN3 transcription, which stabilizes USP25 through deubiquitination, activating an ATXN3-USP25-TRMT1 signaling cascade. This axis enhances TRMT1-mediated tRNA m²<sub>2</sub>G modifications, enabling selective translation of redox-regulating enzymes (e.g., GPX4, SOD2) that scavenge reactive oxygen species (ROS) and mitigate drug-induced oxidative stress. Genetic ablation of TRMT1 or pharmacological targeting of USP25 with the small-molecule inhibitor AZ1 disrupted this pathway, restored ROS accumulation, and re-sensitized resistant tumors to Osimertinib in patient-derived organoids and in vivo models. Our findings reveal tRNA epitranscriptomic reprogramming as a novel mechanism of EGFR-TKI resistance and position the ATXN3/USP25/TRMT1 axis as a therapeutically actionable target to overcome Osimertinib resistance in lung cancer.</p>

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TRMT1-mediated tRNA m22G modification drives Osimertinib resistance via the ATXN3/USP25 axis in lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Jiaqi Li,
  • Bo Jing,
  • Yingying Wang,
  • Wenhui Bai,
  • Qiuyu Wei,
  • Chujiao Zhu,
  • Xuxinyi Ling,
  • Meng Liu,
  • Kuofang Huang,
  • Shifei Pan,
  • Huishu Dong,
  • Haijiao Lu,
  • Jialin Qian,
  • Yanjie Ji,
  • Wanting Liu,
  • Hua Zhong,
  • Youping Zhang,
  • Wenxuan Wu,
  • Yuanhui Zhai,
  • Luo Hao,
  • Hu Lei,
  • Hanzhang Xu,
  • Yingli Wu,
  • Tianqing Chu

摘要

Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), remains a critical challenge in lung adenocarcinoma. Here, we identify ATXN3, a deubiquitinating enzyme, as a driver of Osimertinib resistance and a predictor of poor patient survival. Osimertinib treatment dynamically upregulates ATXN3 transcription, which stabilizes USP25 through deubiquitination, activating an ATXN3-USP25-TRMT1 signaling cascade. This axis enhances TRMT1-mediated tRNA m²2G modifications, enabling selective translation of redox-regulating enzymes (e.g., GPX4, SOD2) that scavenge reactive oxygen species (ROS) and mitigate drug-induced oxidative stress. Genetic ablation of TRMT1 or pharmacological targeting of USP25 with the small-molecule inhibitor AZ1 disrupted this pathway, restored ROS accumulation, and re-sensitized resistant tumors to Osimertinib in patient-derived organoids and in vivo models. Our findings reveal tRNA epitranscriptomic reprogramming as a novel mechanism of EGFR-TKI resistance and position the ATXN3/USP25/TRMT1 axis as a therapeutically actionable target to overcome Osimertinib resistance in lung cancer.