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Updated: Apr 21, 2026

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
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PDK1 elevation was induced by epigenetic modifications of KDM3A and METTL16 to mediate TKI resistance and cancer

Zhihao Zhou1,2, Ruike Zhang1, Zhaoyang Zhang1

  • 1Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan 450000, China.

Genes & Diseases
|April 20, 2026
PubMed

Insights

Pyruvate dehydrogenase kinase 1 (PDK1) drives resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancer. Targeting the KDM3A/METTL16/PDK1 pathway with PDK1 inhibitors offers a promising strategy to overcome TKI resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Lung cancer is a leading cause of cancer mortality worldwide.
  • Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard treatment for EGFR-mutated non-small cell lung cancer.
  • Acquired resistance to EGFR-TKIs is a major clinical challenge.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying acquired resistance to EGFR-TKIs.
  • To identify novel therapeutic targets for overcoming TKI resistance in lung cancer.

Main Methods:

  • Utilized gefitinib- and osimertinib-resistant cell lines.
  • Performed gene knockdown and analyzed protein expression.
  • Investigated mRNA modification and stability.
  • Conducted in vivo studies with PDK1 inhibitors.

Main Results:

  • Pyruvate dehydrogenase kinase 1 (PDK1) was upregulated in TKI-resistant cells and tissues.
  • Knockdown of PDK1 increased sensitivity to TKIs.
  • Histone demethylase KDM3A and METTL16 were involved in PDK1 regulation.
  • PDK1 inhibition synergized with gefitinib to suppress tumor growth in vivo.

Conclusions:

  • The KDM3A/METTL16/PDK1 axis is crucial for cancer development and TKI resistance.
  • This pathway represents a potential therapeutic target for overcoming TKI resistance.
  • PDK1 and its regulators may serve as prognostic biomarkers for TKI resistance.
Keywords:
KDM3AMETTL16PDK1Prognostic biomarkersTKI resistanceTumorigenesis

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