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Updated: Jun 25, 2025

TGF-β-mediated Endothelial to Mesenchymal Transition EndMT and the Functional Assessment of EndMT Effectors using CRISPR/Cas9 Gene Editing
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EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer

Cheng Yang1,2, Shuxiang Ma3, Jie Zhang1,2

  • 1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.

Proceedings of the National Academy of Sciences of the United States of America
|May 30, 2024
PubMed

Insights

Small cell lung cancer (SCLC) transformation drives resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). Suppressing EHMT2 restores TKI sensitivity, offering a therapeutic strategy for overcoming erlotinib resistance in lung adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Lung adenocarcinoma can transform into small cell lung cancer (SCLC), a mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs).
  • Limited clinical samples hinder understanding of resistance mechanisms and development of effective therapies.
  • Preclinical models are crucial for investigating TKI resistance in neuroendocrine (NE) transformation.

Purpose of the Study:

  • To elucidate the transcriptional reprogramming driving resistance to erlotinib in NE transformation.
  • To identify key molecular pathways and potential therapeutic targets for overcoming TKI resistance.

Main Methods:

  • Development of preclinical NE transformation models.
  • Analysis of gene expression in NE transformation cell lines and xenograft models.
  • Investigation of the roles of EHMT2 and WNT/β-catenin pathways in TKI resistance.
  • Validation of findings in clinical SCLC samples.

Main Results:

  • Identified enhanced expression of EHMT2 and WNT/β-catenin pathway genes in NE transformation.
  • Demonstrated that EHMT2-mediated SFRP1 promoter methylation activates the WNT/β-catenin pathway, leading to TKI resistance.
  • Observed similar EHMT2 and SFRP1 expression changes in clinical SCLC samples.
  • Showed that EHMT2 inhibition restores erlotinib sensitivity and delays resistance.

Conclusions:

  • A transcriptional reprogramming mechanism involving EHMT2 and WNT/β-catenin drives erlotinib resistance in NE transformation.
  • EHMT2 is a potential therapeutic target for overcoming TKI resistance in lung adenocarcinoma.
  • Targeting EHMT2 may re-sensitize tumors to erlotinib and improve treatment outcomes.
Keywords:
EHMT2WNT/β-catenin pathwayneuroendocrine transformationnon–small cell lung cancersmall cell lung cancer

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