Abstract
Abstract Breast cancer is the most frequently diagnosed cancer in women. Overexpression of human epidermal growth factor receptors (EGFRs) represents a biological subclass of breast cancer with distinct molecular alterations, clinical behavior, and response to systemic therapy. In this study, we introduce a novel compound (AN019) that has greater anti-tumor activity than Lapatinib. We demonstrate that AN019 is more effective at inhibiting the angiogenic potential and proliferation of both MDAMB231 and HTB20/BT474 cells. FACS analysis shows that AN019 treatment also caused the accumulation of MDAMB231 and HTB20/BT474 cells in the sub-G0/1 phase in a dose-dependent manner; this effect was accompanied by increased PARP cleavage indicative of apoptosis. Strong inhibition of EGFR phosphorylation was also observed in both MDAMB231 and HTB20/BT474 cells. HTB20/BT474 cells did not respond well to Lapatinib treatment when compared to AN019 treatment. From our animal studies using SCID mice implanted with HTB20/BT474 cells, we observed a dose-dependent inhibition of tumor growth when compared to controls or Lapatinib-treated mice at comparable concentrations. A dose-dependent inhibition of EGFR phosphorylation was also observed from immunohistochemical analysis of tumor sections. Our results show that AN019 is superior to Lapatinib in EGFR-overexpressing cells and has strong anti-angiogenic, anti-proliferative and pro-apoptotic properties. In vivo studies demonstrate the increased anti-tumor activity of AN019 over Lapatinib. These results suggest the therapeutic potential of AN019 as anti-angiogenic and anti-proliferative agent in Lapatinib-resistant and EGFR-overexpressing cells. 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 3635.
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