Related Experiment Video

Updated: Jan 30, 2026

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
11:34

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers

Published on: December 5, 2017

13.1K

A recombinant human protein targeting HER2 overcomes drug resistance in HER2-positive breast cancer

Lu Yang1, Yun Li1,2, Arup Bhattacharya1

  • 1Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.

Science Translational Medicine
|January 25, 2019
PubMed

Insights

A novel agent, PEPDG278D, shows promise in overcoming resistance to human epidermal growth factor receptor 2 (HER2) inhibitors in HER2-positive breast cancer. This agent effectively targets HER2, offering a new therapeutic avenue for resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Resistance to human epidermal growth factor receptor 2 (HER2) inhibitors like trastuzumab is a significant challenge in HER2-positive breast cancer (HER2-BC).
  • HER2 overexpression persists in drug-resistant HER2-BC, indicating it remains a viable therapeutic target.

Purpose of the Study:

  • To investigate the potential of PEPDG278D, a mutant of human peptidase D, in overcoming resistance to HER2 inhibitors in HER2-BC.
  • To elucidate the mechanisms by which PEPDG278D exerts its therapeutic effects in resistant HER2-BC models.

Main Methods:

  • Utilized preclinical models of HER2-BC resistant to trastuzumab and other HER2 inhibitors.
  • Assessed the binding of PEPDG278D to HER2 and its effects on HER2 downstream signaling and degradation pathways.
  • Evaluated the combination therapy of PEPDG278D with paclitaxel.

Main Results:

  • PEPDG278D demonstrated high activity in preclinical models of HER2-BC resistant to existing HER2 inhibitors.
  • PEPDG278D binds to HER2, disengages it from Mucin 4, disrupts its interaction with other receptor tyrosine kinases, and promotes HER2 degradation.
  • PEPDG278D also down-regulates epidermal growth factor receptor (EGFR), a contributor to drug resistance, and enhances paclitaxel efficacy.

Conclusions:

  • HER2 remains a critical target in drug-resistant HER2-BC.
  • PEPDG278D exhibits significant therapeutic potential for overcoming resistance to current HER2-targeted therapies in breast cancer.
  • PEPDG278D offers a novel strategy to combat drug resistance in HER2-positive breast cancer.

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