TRIM26-mediated NKRF degradation drives Osimertinib resistance through SNRPD2-dependent stress granule formation in lung adenocarcinoma

  • Cell Death Dis. 2026 Apr 24;17(1):541. doi: 10.1038/s41419-026-08787-x.
Tao Wang  1 ,  Hai-Yan Yang  2 ,  Xing Wang  3 ,  Xin-Hao Han  2 ,  Zhen Zhang  4 ,  Yu Zhang  5 ,  Xiao-Jian Han  6 ,  Zhuo Lu  7  8
Affiliations
  • 1. Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China. [email protected].
  • 2. Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
  • 3. Centre for Medical Research and Translation, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
  • 4. Institute of Clinical Medicine, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China.
  • 5. Institute of Biomedical Innovation, Nanchang University, Nanchang, China.
  • 6. Institute of Geriatrics, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China. [email protected].
  • 7. China-Japan Friendship Jiangxi Hospital, National Regional Center for Respiratory Medicine, Nanchang, China. [email protected].
  • 8. Department of Thoracic Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China. [email protected].
PMID: 42026030 DOI: 10.1038/s41419-026-08787-x
Abstract

Osimertinib is the standard first-line therapy for EGFR-mutant lung adenocarcinoma; however, the inevitable development of acquired resistance leads to disease progression and treatment failure. While established resistance mechanisms primarily involve genetic alterations, stress-adaptive pathways, particularly stress granule-mediated therapeutic tolerance, remain poorly understood. This study aims to elucidate the transcriptional and post-translational mechanisms governing stress granule-mediated survival and their contribution to Osimertinib resistance in lung adenocarcinoma. We identify NF-κB repressing factor (NKRF) as a critical suppressor of Osimertinib resistance, whose expression is markedly reduced in resistant lung adenocarcinoma cells. Restoration of NKRF significantly sensitized resistant cells to Osimertinib in vitro and inhibited tumor growth in xenograft models. Mechanistically, NKRF directly repressed transcription of the ribonucleoprotein component Small nuclear ribonucleoprotein D2 (SNRPD2), thereby constraining stress granule formation and attenuating drug tolerance. We further demonstrate that the E3 ubiquitin Ligase TRIM26 interacts with NKRF and promotes its K48-linked ubiquitination at Lys411, leading to proteasomal degradation. This process sustains SNRPD2 expression and enhances stress granule assembly. Genetic depletion of TRIM26 restored NKRF stability, suppressed stress granule formation, and re-sensitized resistant tumors to Osimertinib, effects that were abrogated by concomitant NKRF silencing. Collectively, this study defines a previously unrecognized TRIM26/NKRF/SNRPD2 regulatory axis that integrates ubiquitin-mediated proteostasis with transcriptional control of stress granule dynamics. This work provides mechanistic insight into stress-adaptive Osimertinib resistance and identifies potential therapeutic targets for overcoming resistance in EGFR-mutant lung adenocarcinoma.

Products