LYMPHOID NEOPLASIA Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor

Although preclinical work with rapalogs suggests potential in treatment of mul-tiple myeloma (MM), they have been less successful clinically. These drugs allo-stearically inhibit the mammalian target of rapamycin kinase primarily curtailing activity of the target of rapamycin com-plex (TORC)1. To assess if the mamma-lian target of rapamycin within the TORC2 complex could be a better target in MM, we tested a new agent, pp242, which prevents activation of TORC2 as well as TORC1. Although comparable to rapamy-cin against phosphorylation of the TORC1 substrates p70S6kinase and 4E-BP-1, pp242 could also inhibit phosphorylation of AKT on serine 473, a TORC2 substrate, while rapamycin was ineffective. pp242 was also more effective than rapamycin in achieving cytoreduction and apoptosis in MM cells. In addition, pp242 was an effective agent against primary MM cells in vitro and growth of 8226 cells in mice. Knockdown of the TORC2 complex pro-tein, rictor, was deleterious to MM cells further supporting TORC2 as the critical target for pp242. TORC2 activation was frequently identified in primary speci-mens by immunostaining for AKT phos-phorylation on serine 473. Potential mechanisms of up-regulated TORC2 activity in MM were stimulation with interleukin-6 or insulin-like growth factor 1, and phosphatase and tensin homolog or RAS alterations. Combining pp242 with bortezomib led to synergistic anti-MM ef-fects. These results support TORC2 as a therapeutic target in MM. (Blood. 2010; 116(22):4560-4568