STRIP2 confers acquired resistance to EGFR-TKIs in lung adenocarcinoma by modulating IGF2BP3-dependent Twist1 stability

  • Genomics. 2026 Jul;118(4):111262. doi: 10.1016/j.ygeno.2026.111262.
Xilin Zhang  1 ,  Jing Gu  2 ,  Ziwei Lei  3 ,  Ruoqian Zhang  2 ,  Yuhang Ling  1 ,  Yanping Xie  2 ,  Chengwu Tang  4 ,  Ying He  5 ,  Weihong Wang  6
Affiliations
  • 1. Central Laboratory, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China.
  • 2. Department of Respiratory Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China.
  • 3. Department of General Practice, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China.
  • 4. Central Laboratory, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
  • 5. Central Laboratory, Huzhou Key Laboratory of Translational Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
  • 6. Department of Respiratory Medicine, First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
PMID: 42191053 DOI: 10.1016/j.ygeno.2026.111262
Abstract

Background: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major obstacle in the treatment of lung adenocarcinoma (LUAD), yet the underlying mechanisms are incompletely understood.

Methods: This study investigated the role of the STRIP2-IGF2BP3 axis in TKI resistance. In vitro and in vivo experiments were performed to evaluate the effect of this axis on TKI sensitivity, the mechanism by which it regulates Twist1 stability, and the prognostic relevance of these markers in LUAD tissue samples.

Results: STRIP2 was upregulated in TKI-resistant patient samples and cells. Knockdown of STRIP2 markedly restored EGFR-TKIs sensitivity both in vitro and in vivo. Mechanistically, STRIP2 cooperated with IGF2BP3 to drive acquired resistance by enhancing m6A modification of Twist1 and stabilizing Twist1 in an IGF2BP3-dependent manner.

Conclusions: These findings highlight that the STRIP2-IGF2BP3-Twist1 axis, which mediates acquired resistance to EGFR-TKIs, represents a potential therapeutic target for LUAD patients.

Keywords
Acquired resistance; Insulin-like growth factor II mRNA binding protein 3; Lung adenocarcinoma; Striatin interacting protein 2; Twist1.
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