577 Characterization of the cellular mechanism of action of the first in class investigational inhibitor of the Ubiquitin Activating Enzyme, MLN7243

Abstract

expression of MET was analyzed by flowcytometry. Processing of MET protein and phosphorylation status of signaling molecules including Akt and S6 ribosomal protein were examined by immunoblot analysis. The in vivo efficacy of M-COPA (50mg/kg, p.o., qd×5) was examined using nude mice bearing xenografted tumors derived from human gastric cancer MKN-45 cells. Results: As expected, MKN-45, a MET-addicted cell line, exhibited a better drug response than those without MET amplification did. Upon treatment with M-COPA, MET expression on the cell surface was dramatically downregulated in a dose response manner. Concurrently, the amount of c-MET precursor form was accumulated; meanwhile cleaved mature form was reduced. Moreover, M-COPA reduced phosphorylated forms of MET and its downstream molecules such as Akt and S6. Finally, we confirmed in vivo antitumor activity of M-COPA against MKN-45 xenografts. Conclusions: M-COPA could be a promising therapy for treating METaddicted tumors by inhibiting the processing and the transport of MET protein onto the cell surface.