Abstract A35: Tyrosine kinase inhibitors block PDGFR-β signaling and suppress growth in malignant endothelial cells

Abstract

Abstract Tyrosine kinase inhibitors (TKIs), including imatinib and dasatinib, have shown remarkable efficacy in controlling chronic myelogenous leukemia and gastrointestinal stromal tumors. Their role in treating other solid tumors is less clear. We are investigating the potential to control malignant endothelial cell (EC) growth with TKIs using a spontaneous canine hemangiosarcoma (HSA) model. Canine HSA is a highly malignant EC cancer with cellular features reminiscent of primitive endothelium. Controlling HSA cell growth has implications for improved outcomes of human and canine patients affected with EC cancer as well as for design of antiangiogenic strategies. We evaluated the effects of imatinib and dasatinib on constitutive tyrosine phosphorylation of platelet derived growth factor receptor-beta (PDGFR-β) that we previously determined to be abnormal in HSA cell cultures. Further, we correlated effects of these TKIs on HSA proliferation in vitro to determine if abnormal activation of PDGFR-β contributes to the HSA malignant phenotype. Dasatinib was approximately ten-fold more potent than imatinib in suppressing HSA cell growth. Dasatinib (100 nM) rapidly abrogated signal from full length and a possible truncated form (120 kDa) of phospho-PDGFR-β. Cells with constitutive activation of PDGFR-β also showed tyrosine phosphorylation of extracellular related kinase-1 (ERK-1), ERK-2, and Src suggesting these could be downstream partners of PDGFR-β in aberrant HSA signaling. Dasatinib markedly suppressed phosphorylation of Src in HSA cells. Taken together; these data suggest that tyrosine kinase inhibitors may affect endothelial cell growth in malignancy by blocking PDGFR-β or its downstream signaling partners. Citation Information: Cancer Res 2009;69(23 Suppl):A35.