Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells |
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Authors: | Norma O’Donovan Annette T Byrne Aisling E O’Connor Sharon McGee William M Gallagher John Crown |
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Institution: | (1) National Institute for Cellular Biotechnology, Dublin City University, Dublin, 9, Ireland;(2) Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, 18, Ireland;(3) UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin, 4, Ireland;(4) Department of Medical Oncology, St. Vincent’s University Hospital, Dublin, 4, Ireland |
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Abstract: | 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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