Response to trastuzumab, erlotinib, and bevacizumab, alone and in combination, is correlated with the level of human epidermal growth factor receptor-2 expression in human breast cancer cell lines
Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that responsiveness to trastuzumab and AG1478 (an anti...
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Published in | Molecular cancer therapeutics Vol. 6; no. 10; pp. 2664 - 2674 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Association for Cancer Research
01.10.2007
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Subjects | |
Online Access | Get full text |
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Summary: | Human epidermal growth factor receptor-2 (HER2) and epidermal growth factor receptor (EGFR) heterodimerize to activate mitogenic
signaling pathways. We have shown previously, using MCF7 subcloned cell lines with graded levels of HER2 expression, that
responsiveness to trastuzumab and AG1478 (an anti-EGFR agent), varied directly with levels of HER2 expression. HER2 and EGFR
up-regulate vascular endothelial growth factor (VEGF), a growth factor that promotes angiogenesis and participates in autocrine
growth-stimulatory pathways that might be active in vitro . Here, we show that trastuzumab, erlotinib, and bevacizumab, individually and in combination, inhibit cell proliferation
in a panel of unrelated human breast cancer cell lines, in proportion to their levels of HER2 expression. The combination
of all three drugs provided a greater suppression of growth than any single drug or two-drug combination in the high HER2–expressing
cell lines ( P < 0.001). Combination index analysis suggested that the effects of these drugs in combination were additive. The pretreatment
net level of VEGF production in each cell line was correlated with the level of HER2 expression ( r = 0.883, P = 0.016). Trastuzumab and erlotinib each reduced total net VEGF production in all cell lines. Multiparameter flow cytometry
studies indicated that erlotinib alone and the triple drug combination produced a prolonged but reversible blockade of cells
in G 1 , but did not increase apoptosis substantially. These studies suggest that the effects of two and three-drug combinations
of trastuzumab, erlotinib, and bevacizumab might offer potential therapeutic advantages in HER2-overexpressing breast cancers,
although these effects are of low magnitude, and are likely to be transient. [Mol Cancer Ther 2007;6(10):2664–74] |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1535-7163 1538-8514 |
DOI: | 10.1158/1535-7163.MCT-07-0079 |