Abstract 5406: ErbB inhibitory protein [EBIP], a modified ectodomain of EGFR, synergizes with dasatinib to inhibit growth of breast cancer cells

Abstract

Abstract It is becoming increasingly evident that many solid tumors including breast cancer show increased activation of several growth factor receptors, specifically EGFR and its family members (EGFRs) as well as c-Src, a non-receptor tyrosine kinase that promote proliferation, inhibit apoptosis and induce metastasis. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for breast cancer. To test our hypothesis we used dasatinib (BMS-354825; Bristol-Myers Squibb), a newly developed highly potent, ATP-competitive Src and Abl kinase inhibitor and ErbB Inhibitory Protein (EBIP) that we generated and found to be an effective pan-ErbB inhibitor. EBIP is composed of 1-448 amino acids of the ectodomain of human EGFR (hEGFR), and the 30 amino acid epitope (known as “U” region) of rat EGFR-Related Protein (ERRP) fused at the carboxy-terminal end. Four different breast cancer cell lines (MDA-MB-468, SKBr-3, MDA-MB-453 and MDA-MB-231) expressing different levels of EGFR and/or its family members were used. Indeed, the combination of dasatinib and EBIP was more effective in inhibiting growth of these breast cancer cell lines than either agent alone. To evaluate further the efficacy of combination therapy we chose MDA-MB-468 cells, which represent triple negative breast cancer. Triple negative breast cancer is characterized by absence of expression of hormone receptors (estrogen receptor; ER and progesterone receptor; PR) and no amplification of HER2. This kind of cancer comprising 15% of all breast cancers, is more frequent among African-American and BRCA1-mutation carriers and is associated with aggressive histology and poor prognosis. In EGFR overexpressing MDA-MB-468 cells, the combination therapy caused a greater induction of apoptosis by activating caspases −9 and 8 and attenuating EGFR and c-Src signaling. The combination therapy was greatly effective in inhibiting aggressive behavior of MDA-MB-468 as evidenced by (a) decreased extracellular invasion (b) colony formation and (c) tubule formation by endothelial cells. Furthermore, the combination therapy was highly effective in inhibiting the growth of xenografts of MDA-MB-468 cells in SCID mice, which could be attributed to inhibition of proliferation and induction of apoptosis, accompanied by decreased activation of EGFR and c-Src. In conclusion, our data suggest that combination treatment of dasatinib and EBIP that target EGFRs and Src could be a highly effective therapeutic strategy for breast cancer, with particular reference to triple negative breast cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5406.