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Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
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Related Experiment Video

Updated: Apr 15, 2026

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
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Novel agents that downregulate EGFR, HER2, and HER3 in parallel.

Renan Barroso Ferreira1, Mary Elizabeth Law2, Stephan Christopher Jahn2

  • 1Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.

Oncotarget
|April 14, 2015
PubMed
Summary

New Disulfide Bond Disrupting Agents (DDAs) show promise in killing cancer cells by targeting EGFR, HER2, and HER3. These novel compounds may overcome resistance to existing cancer therapies.

Keywords:
EGFRHER2HER3breast cancerdisulfide bonds

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Epidermal Growth Factor Receptor (EGFR), Human Epidermal growth factor Receptor 2 (HER2), and Human Epidermal growth factor Receptor 3 (HER3) are key drivers in human cancer development and progression.
  • Resistance to current therapies, including monoclonal antibodies and tyrosine kinase inhibitors, often stems from functional redundancy among EGFR, HER2, and HER3.
  • These receptor tyrosine kinases share conserved extracellular structures stabilized by disulfide bonds, presenting a potential vulnerability.

Purpose of the Study:

  • To identify novel compounds capable of simultaneously inactivating EGFR, HER2, and HER3 by disrupting their extracellular disulfide bonds.
  • To evaluate the efficacy of these compounds in eliminating cancer cells, particularly those overexpressing EGFR or HER2.
  • To explore the potential of these Disulfide Bond Disrupting Agents (DDAs) as a complementary therapeutic strategy to overcome resistance in cancer treatment.

Main Methods:

  • Screening for compounds that induce cell death in breast cancer cell lines overexpressing EGFR or HER2.
  • Assessing the effect of identified compounds on the expression levels of EGFR, HER2, and HER3.
  • Characterizing the mechanism of action, specifically the disruption of extracellular disulfide bonds.
  • Evaluating the in vivo anticancer efficacy and toxicity of lead compounds, such as DDA RBF3.

Main Results:

  • Identification of Disulfide Bond Disrupting Agents (DDAs) that effectively kill breast cancer cells overexpressing EGFR or HER2.
  • Observed parallel downregulation of EGFR, HER2, and HER3 expression correlating with cell death induced by DDAs.
  • Demonstrated in vivo anticancer efficacy of DDA RBF3 at 40 mg/kg without observable toxicity.
  • Confirmed that DDAs function by disrupting critical disulfide bonds within the extracellular domains of EGFR, HER2, and HER3.

Conclusions:

  • Disulfide Bond Disrupting Agents (DDAs) represent a novel class of anticancer compounds targeting the EGFR family.
  • DDAs effectively induce cancer cell death by disrupting essential disulfide bonds, leading to the downregulation of EGFR, HER2, and HER3.
  • DDA RBF3 shows promising in vivo efficacy and safety, suggesting its potential as a therapeutic agent.
  • DDAs may serve as valuable adjuncts to existing targeted therapies, potentially overcoming therapeutic resistance through combination regimens.