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EGFR over-expression and activation in high HER2, ER negative breast cancer cell line induces trastuzumab resistance

Rajiv Dua1, Jianhuan Zhang, Phets Nhonthachit

  • 1Oncology, Monogram Biosciences, 345 Oyster Point Blvd, South San Francisco, CA, USA. rdua@monogrambio.com

Breast Cancer Research and Treatment
|October 28, 2009
PubMed

Insights

Epidermal Growth Factor Receptor (EGFR) overexpression can cause resistance to trastuzumab (Herceptin) in HER2-positive breast cancer. High EGFR levels, not moderate, induce trastuzumab resistance, which can be reversed by targeting EGFR.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • HER2 (Human Epidermal growth factor Receptor 2) amplification/overexpression occurs in 20-25% of breast cancers, leading to elevated HER2 activation.
  • Trastuzumab (Herceptin) is a monoclonal antibody effective against HER2-overexpressing breast cancers, but resistance develops over time.
  • Resistance mechanisms include HER2 pathway inactivation or upregulation of alternative receptors like EGFR (Epidermal Growth Factor Receptor).

Purpose of the Study:

  • To investigate the role of EGFR overexpression in acquired trastuzumab resistance in ER-negative breast carcinoma cell lines.
  • To determine the threshold level of EGFR required to induce trastuzumab resistance.

Main Methods:

  • Generation of SKBR3 cell line clones with varying EGFR expression levels.
  • Assessment of trastuzumab sensitivity in EGFR-overexpressing clones.
  • Depletion of EGFR using small-interfering RNAs (siRNAs).
  • Evaluation of sensitivity to lapatinib, an EGFR/HER2 inhibitor.
  • Biochemical analysis including co-immunoprecipitation and VeraTag assays to study EGFR phosphorylation and dimerization.

Main Results:

  • A clone with high EGFR expression (SKBR3/EGFR clone 5) developed resistance to trastuzumab, while a clone with moderate EGFR expression (SKBR3/EGFR clone 4) remained sensitive.
  • EGFR depletion reversed trastuzumab resistance in the resistant clone.
  • The resistant clone remained sensitive to lapatinib.
  • High EGFR levels correlated with increased EGFR phosphorylation, EGFR homodimerization, and EGFR/HER2 heterodimerization.

Conclusions:

  • EGFR overexpression can mediate trastuzumab resistance in both ER-positive and ER-negative breast cancer cells.
  • A threshold level of EGFR, independent of autocrine ligand production, appears necessary to induce trastuzumab resistance.
  • Targeting EGFR, potentially with dual inhibitors like lapatinib, may overcome trastuzumab resistance.

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