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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

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NAT10-mediated lipid metabolic reprogramming drives EGFR-TKI resistance in non-small cell lung cancer via

Shuai Fang1, Yuchao Zhu2, Wei Chen1,3

  • 1Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, People's Republic of China.

Experimental Hematology & Oncology
|November 28, 2025
PubMed

Insights

Epigenetic therapy using Remodelin enhances sensitivity to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC). Targeting NAT10, an enzyme overexpressed in NSCLC, may overcome treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance is a major challenge in non-small cell lung cancer (NSCLC) treatment.
  • Epigenetic modifications play a role in cancer development and drug resistance.
  • Identifying novel therapeutic targets is crucial for overcoming EGFR-TKI resistance.

Purpose of the Study:

  • To investigate the potential of epigenetic therapy in overcoming EGFR-TKI resistance in NSCLC.
  • To identify specific epigenetic targets and drugs that can re-sensitize NSCLC cells to EGFR-TKIs.
  • To elucidate the molecular mechanisms underlying NAT10-mediated EGFR-TKI resistance.

Main Methods:

  • Screening of an epigenetic drug library to identify compounds enhancing EGFR-TKI sensitivity.
  • Assessment of NAT10 expression in NSCLC tissues and correlation with patient prognosis.
  • In vitro and in vivo experiments involving NAT10 knockdown and Remodelin treatment.
  • Analysis of mRNA modification (ac4C) and gene expression (FATP4, CPT1A).
  • Investigation of upstream regulators of NAT10 transcription (p300, H3K27ac).

Main Results:

  • Remodelin was identified as a potent enhancer of EGFR-TKI sensitivity in NSCLC cells.
  • NAT10 was found to be overexpressed in NSCLC and associated with poor prognosis.
  • NAT10 knockdown inhibited NSCLC proliferation, increased apoptosis, and enhanced EGFR-TKI sensitivity.
  • NAT10 promotes EGFR-TKI resistance by enhancing fatty acid metabolism via ac4C modification of FATP4 and CPT1A mRNA.
  • p300-mediated H3K27ac acetylation regulates NAT10 transcription.
  • Remodelin combined with gefitinib showed significant antitumor efficacy in vivo.

Conclusions:

  • NAT10 is a key driver of EGFR-TKI resistance in NSCLC through fatty acid metabolism remodeling.
  • Targeting NAT10 presents a promising therapeutic strategy to overcome EGFR-TKI resistance.
  • Remodelin demonstrates potential as an adjuvant therapy to enhance EGFR-TKI efficacy in NSCLC patients.
Keywords:
EGFR-TKI resistanceLipid metabolism reprogrammingNAT10NSCLCac4C modification

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