Related Experiment Video

Updated: Jul 1, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

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

Jiaqi Li1,2, Bo Jing3, Yingying Wang4

  • 1Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cell Death & Disease
|June 29, 2026
PubMed

Insights

Acquired resistance to Osimertinib in lung cancer is driven by ATXN3 stabilizing USP25, impacting tRNA modifications. Targeting this ATXN3/USP25/TRMT1 axis can overcome resistance and improve patient survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Acquired resistance to Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), is a significant clinical problem in lung adenocarcinoma.
  • Understanding the molecular mechanisms underlying this resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To identify novel molecular drivers of Osimertinib resistance in lung adenocarcinoma.
  • To elucidate the signaling pathways involved in resistance and explore potential therapeutic targets.

Main Methods:

  • Utilized patient-derived organoids and in vivo models to study Osimertinib resistance.
  • Investigated the role of the deubiquitinating enzyme ATXN3 and its downstream targets.
  • Assessed the impact of genetic ablation and pharmacological inhibition on drug sensitivity.

Main Results:

  • Identified ATXN3 as a key driver of Osimertinib resistance, correlating with poor patient survival.
  • Demonstrated that Osimertinib treatment upregulates ATXN3, which stabilizes USP25, activating an ATXN3-USP25-TRMT1 cascade.
  • Showed that this cascade enhances tRNA modifications, promoting the translation of redox-regulating enzymes that mitigate oxidative stress.
  • Found that targeting TRMT1 or USP25 restored ROS accumulation and re-sensitized resistant tumors to Osimertinib.

Conclusions:

  • Discovered a novel mechanism of EGFR-TKI resistance involving tRNA epitranscriptomic reprogramming.
  • Established the ATXN3/USP25/TRMT1 axis as a critical pathway mediating Osimertinib resistance.
  • Positioned this axis as a promising therapeutic target to overcome Osimertinib resistance in lung cancer.

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