Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling by the dual tyrosine kinase inhibitor AEE788 and paclitaxel as therapy for human follicular thyroid cancer bone metastasis in nude mice

Abstract

Patients suffering from bone metastases of Follicular Thyroid Carcinoma (FTC) have a poor prognosis because of the lack of effective treatment strategies. The overexpression of Epidermal Growth Factor Receptor (EGFR) associated with increased vascularity has been implicated in the pathogenesis of FTC and subsequent bone metastases. We hypothesized that inhibiting the phosphorylation of the EGFR and Vascular Endothelial Growth Factor Receptor (VEGFR) by AEE788, a dual tyrosine kinase inhibitor of EGFR and VEGFR, in combination with paclitaxel would inhibit experimental FTC bone lesions and preserve bone structure. We tested this hypothesis in the human WRO FTC cell line. In culture, AEE788 inhibited the EGF-mediated phosphorylation of EGFR, VEGFR, Mitogen-activated Protein Kinase (MAPK) and AKT in WRO cells. AEE788, alone and in combination with paclitaxel, inhibited cell growth and induced apoptosis in the tumor cells. After WRO cells were injected into the tibia of nude mice, WRO tumors and endothelial cells within these lesions expressed phosphorylated EGFR, VEGFR, AKT and MAPK that could be inhibited by the oral administration of AEE788. Therapy consisting of orally administered AEE788 and intraperitoneally injected paclitaxel induced a high level of apoptosis in tumor vascular endothelial cells and tumor cells that correlated with the inhibition of tumor growth in the bone and the preservation of bone structure. Collectively, these data showed that blocking the phosphorylation of EGFR and VEGFR with AEE788 in combination with administering paclitaxel can significantly inhibit experimental human FTC bone metastasis