Many solid
tumors, including
breast cancer, show increased activation of several
growth factor receptors, specifically
epidermal growth factor receptor (EGFR) and its family members as well as c-Src, a nonreceptor
tyrosine kinase that promotes proliferation, inhibits apoptosis, and induces
metastasis. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for
triple-negative breast cancer. To test our hypothesis, we used a c-Src-specific inhibitor
dasatinib (
BMS-354825; Bristol-Myers Squibb) and our newly developed
ErbB-inhibitory protein (EBIP), a potential pan-ErbB inhibitor, in
breast cancer cells. EBIP is composed of 1 to 448
amino acids of the ectodomain of human EGFR to which the 30-amino
acid epitope (known as "U" region) of rat EGFR-related
protein is fused at the COOH-terminal end. The combination of
dasatinib and EBIP was found to be highly effective in inhibiting the growth of four different
breast cancer cells (MDA-MB-468, SKBr-3, MDA-MB-453, and MDA-MB-231) that express different levels of EGFRs. In EGFR-overexpressing MDA-MB-468 cells, the combination, but not monotherapy, markedly stimulated apoptosis mediated by
caspase-9 and
caspase-8 and attenuated activation of EGFR and Src as well as
tyrosine kinase activity. EBIP also inhibited
heregulin-induced activation of HER-2 and HER-3 in MDA-MB-453
breast cancer cells. The combination
therapy was highly effective in suppressing
tumor growth ( approximately 90% inhibition) in MDA-MB-468-derived xenografts in severe combined immunodeficient mice. The latter could be attributed to induction of apoptosis. We conclude that combining
dasatinib and EBIP could be an effective therapeutic strategy for
breast cancer by targeting EGFRs and Src signaling.