Abstract 1050: Lapatinib suppresses RTK-mediated signaling through multiple signaling pathways in the chemically-induced ER+ model of mammary cancer

Abstract

Abstract Activation of tyrosine kinase receptors, including EGFR, HER2, HER3 and HER4, plays a key role in the prognosis of mammary cancer. EGFR and HER2 are validated therapeutic targets; but unfortunately, only a small percentage of patients with EGFR or HER2-overexpressing tumors respond to therapy, and resistance develops even in responsive patients. Lapatinib is a small molecule dual tyrosine kinase inhibitor that suppresses the activation of EGFR and HER2. Completely understanding the molecular mechanisms and protein targets involved in the effects of Lapatinib and other RTK inhibitors can help determine why efficacy varies as well as identify biomarkers which may be indicative of effective therapy. This requires the simultaneous identification of specific molecular markers in the complex network of signaling pathways that are modulated by Lapatinib in mammary cancer. The purpose of this study was to identify potential direct and indirect protein targets modified by Lapatinib treatment. Female Sprague-Dawley rats (50 d) were given methylnitroso-urea (MNU) by IV injection via jugular vein (75 mg/kg BW). Rats developed multiple ER+ tumors. Two different approaches were taken to evaluate the efficacy of Lapatinib as either a chemopreventive or chemotherapeutic drug. First we demonstrated that treatment with Lapatinib beginning 5 days after MNU was highly effective in preventing tumor development. In addition, we treated rats with palpable mammary tumors with Lapatinib (75 mg/kg BW/day). In some of the tumor bearing animals, treatment proceeded for 42 days, and therapeutic results were obtained. In a separate group, rats bearing tumors were treated for 5 days and the resulting lesions examined for biomarker modulation. Female Sprague-Dawley rats (50 d) were given methylnitroso-urea (MNU) by IV injection via jugular vein (75 mg/kg BW). Rats developed multiple ER+ tumors. Two different approaches were taken to evaluate the efficacy of Lapatinib as either a chemopreventive or chemotherapeutic drug. First we demonstrated that treatment with Lapatinib beginning 5 days after MNU was highly effective in preventing tumor development. In addition, we treated rats with palpable mammary tumors with Lapatinib (75 mg/kg BW/day). In some of the tumor bearing animals, treatment proceeded for 42 days, and therapeutic results were obtained. In a separate group, rats bearing tumors were treated for 5 days and the resulting lesions examined for biomarker modulation. These results suggest that RTK inhibitors have a wide range of potential targets. More work is in progress to continue the dissection of the action of Lapatinib and other RTK inhibitors. Supported by The Hormel Foundation and NCI Contract Number HHSN-261200433009C – NO1-CN-55006-72. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1050. doi:10.1158/1538-7445.AM2011-1050