Abstract A93: Lapatinib suppresses RTK-mediated signaling through multiple signaling pathways in the chemically induced ER+ model of mammary cancer

Abstract

Abstract Activation of receptor tyrosine kinases (RTKs) plays a key role in the prognosis of mammary cancer. EGFR and HER2 are validated therapeutic targets. Lapatinib is a small molecule dual RTK inhibitor that targets EGFR and HER2. Identifying the protein targets involved in the effects of lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats (50 days old) were given methylnitrosourea (MNU) by IV injection through the jugular vein (75 mg/kg BW). The 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 (75mg/KgBW/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 biomarkers modulation. Lapatinib caused a marked inhibition of mammary cancers, and effectively suppressed the abundance of both HER2, phosphorylated HER2 (Tyr1221, Tyr1222) and phosphorylated EGFR (Tyr1173, Tyr1110) compared to tumors from untreated control rats. Protein array analyses allowed parallel determination of the effect of lapatinib on the relative levels of protein phosphorylation and apoptosis. Interestingly, unlike Gefitinib (Iressa), which appears to target EGFR signaling mediated primarily through the ERK MAP kinases, lapatinib seems to suppress EGFR/HER2 signaling primarily through Src-related proteins, Lyn and Lck, Akt and GSK3. The complete signaling cascade involves a number of signaling molecules potentially leading to impaired proliferation, apoptosis or cell cycle arrest. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A93.