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Updated: Jun 18, 2025

Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
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Peptidylarginine deiminase 3 modulates response to neratinib in HER2 positive breast cancer

Inés Romero-Pérez1,2, Elena Díaz-Rodríguez1,2,3, Laura Sánchez-Díaz1,2

  • 1Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Salamanca, Spain.

Oncogenesis
|August 3, 2024
PubMed

Insights

Neratinib resistance in HER2+ breast cancer can be overcome by targeting peptidylarginine deiminase 3 (PADI3). Overexpressing PADI3 confers resistance, while inhibiting it restores sensitivity to neratinib therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Neratinib is a tyrosine kinase inhibitor for HER2+ breast cancer.
  • Acquired resistance limits neratinib's long-term efficacy.
  • Understanding resistance mechanisms is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the molecular mechanisms of neratinib resistance in HER2+ breast cancer cells.
  • To identify novel therapeutic targets for overcoming neratinib resistance.

Main Methods:

  • Development of neratinib-resistant cell lines (BT474) via chronic drug exposure.
  • Biochemical and biological characterization of resistant clones.
  • Transcriptomic and Western blot analyses to identify differentially expressed proteins.
  • Gene knockdown and overexpression studies to assess PADI3 function.

Main Results:

  • Neratinib-resistant clones retained HER2 dependency and sensitivity in tyrosine phosphorylation.
  • Peptidylarginine deiminase 3 (PADI3) was significantly overexpressed in resistant clones.
  • PADI3 knockdown restored neratinib sensitivity, while PADI3 overexpression induced resistance.

Conclusions:

  • PADI3 plays a critical role in regulating neratinib sensitivity in HER2+ breast cancer.
  • PADI3 inhibition represents a potential therapeutic strategy to combat neratinib resistance.

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