Lapatinib and sunitinib on glioma cell migration through implication of growth factor with integrins.

Abstract

e12527 Background: Malignant gliomas are the most common and aggressive primary brain tumors. Sunitinib is an oral, small-molecule, multi-targeting receptor tyrosine kinase inhibitor (TKI), including platelet-derived growth factor receptors (PDGFR) and vascular endothelial growth factor receptors (VEGFR). Lapatinib is an ATP-competitive dual TKI for epidermal growth factor receptor (EGFR) and HER2/neu (ErbB-2). The aim of this study was to assess the antitumor effect of sunitinib and lapatinib applied either alone or in combination on two glioma cell lines. We previously showed that sunitinib and lapatinib have an antiproliferative effect in U87 and M059K glioma cell lines. In the current setting, we focused on the effect of each agent in cell migration. Furthermore, we sought to evaluate the effect of lapatinib in the formation of EGFR-integrin β1 complex, as well as the effect of sunitinib in the VEGFR-integrin β3 and PDGFR-integrin β3 complexes formation. Methods: U87 and M059K cells were cultured as recommended by ATCC. Migration assays were performed in chambers, using uncoated polycarbonate membranes. Immunoprecipitation and western blot analysis were used for studying the complex formation of EGFR, PDGFR and VEGFR with integrins. The protein localization was evaluated through immunofluorescence assay. Results: We found that both agents administered either alone or in combination, reduced the ability of U87 and M059K cells to migrate 4 h after their application. The time course study of the effect of lapatinib on EGFR-integrin β1 complex revealed an inhibition in complex formation up to 30 min after the application of the agent. Likewise, sunitinib inhibited complex formation of VEGFR-integrin β3 and PDGFR-integrin β3 complexes within 2h after its application. The previously-described interruption of complexes formation was confirmed with an immunofluorescence assay. The experiments with M059K cells are still ongoing. Conclusions: The preliminary results of our study are the first to support the implication of an anti-EGFR agent, lapatinib and a multi-targeted agent, sunitinib in glioma cells migration, through a mechanism implying interruption of growth factor-integrin complexes formation. No significant financial relationships to disclose.