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Updated: May 7, 2026

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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HDAC1 Regulates Acquired Resistance to EGFR Inhibitors through the TFCP2-NDRG1 Signaling Axis in Pancreatic Cancer

Taoyu Chen1,2, Yuxuan Li1,2, Yan Sun3

  • 1Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.

International Journal of Biological Sciences
|May 6, 2026
PubMed

Insights

Histone deacetylase 1 (HDAC1) drives resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in pancreatic cancer by suppressing TFCP2. Inhibiting HDAC1 or restoring TFCP2 acetylation overcomes this resistance.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are crucial for pancreatic ductal adenocarcinoma (PDAC) treatment.
  • Acquired resistance limits the clinical effectiveness of EGFR-TKIs like erlotinib in PDAC.
  • Understanding resistance mechanisms is vital for improving therapeutic strategies.

Purpose of the Study:

  • To identify key epigenetic drivers of erlotinib resistance in PDAC.
  • To elucidate the molecular mechanisms underlying EGFR-TKI resistance.
  • To explore novel therapeutic strategies targeting resistance pathways.

Main Methods:

  • Analysis of histone deacetylase 1 (HDAC1) expression in erlotinib-resistant PDAC cells.
  • Investigation of HDAC1's role in regulating transcription factor TFCP2 acetylation and function.
  • Assessment of TFCP2's impact on NDRG1 and EGFR expression.
  • Evaluation of EGFR-mediated phosphorylation in HDAC1 stability.
  • Design and testing of a TFCP2-derived peptide inhibitor.
  • In vitro and in vivo validation of HDAC1 inhibition and TFCP2 restoration.

Main Results:

  • HDAC1 is significantly upregulated in erlotinib-resistant PDAC cells.
  • HDAC1 directly suppresses TFCP2 transcriptional activity via deacetylation at K256.
  • TFCP2 suppression leads to reduced NDRG1 and increased EGFR expression, promoting resistance.
  • EGFR signaling stabilizes HDAC1 through protection from the ubiquitin-proteasome system.
  • A TFCP2-derived peptide effectively inhibits HDAC1 activity and restores TFCP2 function.
  • Pharmacological HDAC1 inhibition or TFCP2 acetylation restoration reverses erlotinib resistance.

Conclusions:

  • HDAC1 is a critical epigenetic mediator of acquired resistance to EGFR-TKIs in PDAC.
  • A feedback loop involving EGFR signaling and HDAC1 stabilization sustains resistance.
  • Targeting HDAC1 or restoring TFCP2 acetylation represents a promising therapeutic strategy for overcoming erlotinib resistance in PDAC.
Keywords:
PDACerlotinib resistancehistone deacetylase1therapeutic strategytranscription factor CP2

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