Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies.

Abstract

Since the discovery of rapamycin in Easter Island soil in 1975, more has been learnt about the relevance and importance of the mammalian target of rapamycin (mTOR) pathway in cell signalling, proliferation and ultimately tumourigenesis. Rapamycin targets the mTORC1 complex alone. Despite initial excitement, rapamycin and its analogues, everolimus and temsirolimus, have displayed limited efficacy in the treatment of lymphoid malignancies. This review highlights the important and well-described aspects of the critical phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway and discusses the mechanisms of action of rapamycin, its clinical efficacy in lymphoid malignancies, and the mechanisms of resistance. Renewed interest in targeting the pathway has evolved through the discovery of mTORC2, a protein complex associated with a key mechanism of resistance to first generation mTOR inhibitors. As such, novel dual inhibitors of mTORC1 and mTORC2 have been developed, along with other dual inhibitors of the mTOR pathway. The evolution in the development of dual inhibitors is described herein, along with the burgeoning in vitro, pre-clinical data and the early phase clinical data available. Although historically mTOR inhibitors have been used extensively in haematopoietic and solid organ transplant prophylaxis, this review will focus on developments of their use in lymphoid malignancies.