Identification and Characterization of Inhibitors That Specifically Target TORC2 in Multiple Myeloma

Abstract 5026

Recent data indicate that TORC2 is necessary for survival of multiple myeloma (MM) cells. Currently, drugs targeting mTOR either inhibit TORC1 alone or both TORC1 and TORC2. To identify drugs that specifically target TORC2, we performed a drug screen in a yeast-two hybrid system to identify compounds that prevented an interaction between rictor and mTOR. We identified several potential compounds and have begun to characterize their molecular activity. These compounds induced significant MM cell apoptosis when used at concentrations below 4 uM. This cytotoxic effect was accomplished by a down regulation of TOR activity which was specific for TORC2 (ie., decreased S473 AKT phosphorylation and NDRG T346 phosphorylation). Co-immunoprecipitation experiments confirmed that at least some of the compounds prevented binding of rictor to mTOR within MM cells while having no effect on binding of raptor to mTOR. In addition, myeloma cells expressing TORC2 phosphomimetic protein substrates (AKTS473D or SGKS422D) were significantly less sensitive to apoptosis as compared to the empty vector control when treated with these compounds. These data suggest that the drug-induced cytotoxicity was mediated specifically through the inhibition of TORC2 kinase activity. These results are the initial characterization of TORC2-specific drugs and support a rationale for targeting TORC2 in multiple myeloma.