Targeting mTOR in mantle cell lymphoma: current and future directions.

The PI3K/Akt/mTOR pathway is an important therapeutic target in mantle cell lymphoma. Ample preclinical data suggests this axis contributes not only to pathogenesis, but remains tonically activated and can be targeted with available agents. Classic mTOR inhibitors, which allosterically bind to mTORC1 and include temsirolimus and everolimus, show efficacy in heavily pretreated and elderly patients. However, only a portion of patients respond and durability is limited. Numerous resistance mechanisms have been identified, including paradoxical Akt activation. Currently, several ongoing trials are combining mTOR inhibitors with other agents that either block upstream components of the PI3K/Akt/mTOR axis or that inhibit complementary signaling pathways, with hopes of improving outcomes. Dual inhibition of mTORC1 and mTORC2 using small molecule catalytic site inhibitors against the mTOR kinase may also prove to be superior to first generation agents, but clinical data remains nascent. Several dozen ongoing clinical trials should help refine the optimal use of mTOR inhibitors for MCL patients.