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 G₁ 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 G₁ 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.