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The splicing factor hnRNPA1 promotes osimertinib resistance in lung adenocarcinoma by regulating NEDD4L alternative

Yanfeng Liang1, Yudong Guo2, Xiaobi Huang1

  • 1Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.

Oncogene
|June 19, 2026
PubMed

Insights

Splicing factor hnRNPA1 drives osimertinib resistance in lung adenocarcinoma by altering NEDD4L splicing. Silencing hnRNPA1 restores sensitivity, identifying it as a therapeutic target for lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Osimertinib resistance is a major challenge in lung adenocarcinoma treatment.
  • Aberrant alternative splicing contributes to cancer progression and drug resistance.
  • The precise role of splicing factors in osimertinib resistance remains unclear.

Purpose of the Study:

  • To investigate the role of splicing factor hnRNPA1 in osimertinib resistance in lung adenocarcinoma.
  • To elucidate the molecular mechanisms by which hnRNPA1 mediates this resistance.

Main Methods:

  • Small interfering RNA (siRNA) and CDX models were used to assess hnRNPA1 function.
  • RNA-sequencing (RNA-seq), RNA immunoprecipitation (RIP), and crosslinking immunoprecipitation (CLIP-qPCR) were employed.
  • Co-immunoprecipitation (COIP) and virtual docking were utilized to explore molecular interactions and potential drug targets.

Main Results:

  • Elevated hnRNPA1 levels correlated with osimertinib resistance in lung adenocarcinoma cells.
  • hnRNPA1 silencing resensitized resistant cells to osimertinib.
  • hnRNPA1 regulates NEDD4L splicing, leading to EGFR degradation and restored sensitivity.
  • PRMT7-mediated methylation of hnRNPA1 enhances its splicing activity.

Conclusions:

  • Aberrant splicing driven by hnRNPA1 is a key mechanism of osimertinib resistance in lung cancer.
  • Targeting hnRNPA1, potentially with natural small-molecule drugs, offers a promising strategy to overcome osimertinib resistance.

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