Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma, with a mean survival of only 3-5 years and suboptimal therapeutic options. MCL is characterized by a balanced translocation t(11;14)( q13; q32), resulting in overexpression of cyclin D1, a G(1) cyclin regulated by the PI3K/Akt/mammalian target of rapamycin ( mTOR) signaling pathway. As improved therapy for MCL is required and the mTOR pathway may be involved in its pathophysiology, the antiproliferative effects of RAD001 ( everolimus), an mTOR inhibitor, against three MCL cell lines were investigated. As a single agent, RAD001 inhibited proliferation in MCL cell lines (Jeko1, SP49 and NCEB1) approximately 40-65% compared to diluent control cells. This was associated with G(1) cell-cycle arrest and reduced phosphorylation of the mTOR downstream target, 4E-BP1. Furthermore, combination drug studies revealed predominantly synergistic cytotoxicity with RAD001 and several secondary agents, including doxorubicin, vincristine or rituximab ( components of the standard MCL regimen), as well as paclitaxel, vorinostat and bortezomib. These data indicate that single agent RAD001 is effective in inhibiting growth of MCL cells in vitro and combination studies with secondary agents further demonstrate synergistic cytotoxicity. Thus, these findings support future clinical studies of RAD001 in the treatment of MCL.