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Time now to TORC the TORC ? New developments in m TOR pathway inhibition in lymphoid malignancies
Author(s) -
Eyre Toby A.,
Collins Graham P.,
Goldstone Anthony H.,
Cwynarski Kate
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12945
Subject(s) - pi3k/akt/mtor pathway , mtorc1 , mtorc2 , everolimus , mechanistic target of rapamycin , cancer research , protein kinase b , temsirolimus , rptor , biology , signal transduction , medicine , microbiology and biotechnology , discovery and development of mtor inhibitors , oncology
Summary 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 (m TOR ) pathway in cell signalling, proliferation and ultimately tumourigenesis. Rapamycin targets the m TORC 1 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/m TOR 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 m TORC 2, a protein complex associated with a key mechanism of resistance to first generation mTOR inhibitors. As such, novel dual inhibitors of m TORC 1 and mTORC 2 have been developed, along with other dual inhibitors of the m TOR 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 m TOR inhibitors have been used extensively in haematopoietic and solid organ transplant prophylaxis, this review will focus on developments of their use in lymphoid malignancies.