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Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

Investigational New Drugs volume 29, pages 752–759 (2011)Cite this article

Summary

Overexpression of HER-2 in breast cancer is frequently associated with expression of EGFR, and EGFR expression influences response to HER-2 inhibition. The aim of this study was to examine the effects of combining dual inhibition of EGFR and HER-2, using trastuzumab, gefitinib and lapatinib, in HER-2 overexpressing breast cancer cells. Combination proliferation assays were performed in two HER-2 positive breast cancer cell lines, SKBR-3 and BT-474. Trastuzumab combined with lapatinib was also tested in BT-474 xenografts. In proliferation assays, dual targeting with trastuzumab and gefitinib or lapatinib showed synergy or additivity in both SKBR-3 and BT-474 cells. Trastuzumab (10 nM) or gefitinib (5 µM) alone did not induce significant apoptosis, whereas lapatinib (0.75 µM) induced significant apoptosis in SKBR-3 cells. Trastuzumab combined with lapatinib further enhanced apoptosis induction. Trastuzumab (10 nM) and gefitinib (5 µM) induced apoptosis comparable to lapatinib alone (0.75 µM), suggesting that inhibition of both EGFR and HER-2 may be required to induce apoptosis in these cells. Pre-treatment with trastuzumab and gefitinib or lapatinib enhanced response to chemotherapy in vitro. The combination of trastuzumab and lapatinib also effectively blocked tumour growth in vivo. Dual targeting of EGFR and HER-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.

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Acknowledgements

This research was supported by the Cancer Clinical Research Trust, the Health Research Board (CSA/2007/11) and the Science Foundation Ireland funded Molecular Therapeutics for Cancer Ireland (www.mtci.ie, 08/SRC/B1410). We wish to acknowledge technical assistance provided by UCD CIBS staff for the in vivo study.

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Affiliations

  1. National Institute for Cellular Biotechnology, Dublin City University, Dublin, 9, Ireland

    Norma O’Donovan & John Crown

  2. Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, 18, Ireland

    Annette T. Byrne

  3. UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, 4, Ireland

    Aisling E. O’Connor, Sharon McGee & William M. Gallagher

  4. Department of Medical Oncology, St. Vincent’s University Hospital, Dublin, 4, Ireland

    John Crown

Authors
  1. Norma O’Donovan
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  2. Annette T. Byrne
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  3. Aisling E. O’Connor
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  4. Sharon McGee
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  5. William M. Gallagher
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  6. John Crown
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Corresponding author

Correspondence to Norma O’Donovan.

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Supplementary Figure 1

Proliferation assays of BT-474 cells treated with trastuzumab (T) and gefitinib (G) or trastuzumab and lapatinib (L) in combination with taxanes. Cells were pre-treated with T (0.25 nM) and G (125 nM) or T (0.33 nM) and L (25 nM) for 24 h prior to addition of taxanes for 4 days. Proliferation was assessed using the acid phosphatase assay (DOC 53 kb)

Supplementary Table 1

Percentage growth of SKBR-3 and BT-474 cells treated with EGFR/HER-2 inhibitors alone or platinum drugs alone and combinations of trastuzumab with gefitinib or lapatinib for 24 h followed by cisplatin or carboplatin for 4 days (DOC 60 kb)

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O’Donovan, N., Byrne, A.T., O’Connor, A.E. et al. Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Invest New Drugs 29, 752–759 (2011). https://doi.org/10.1007/s10637-010-9415-5

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  • DOI: https://doi.org/10.1007/s10637-010-9415-5

Keywords

  • Breast tumour
  • ErbB2
  • Epidermal growth factor receptor
  • Gefitinib
  • Herceptin
  • Lapatinib