Related Experiment Videos
Time now to TORC the TORC? New developments in mTOR pathway inhibition in lymphoid malignancies
Toby A Eyre1, Graham P Collins, Anthony H Goldstone
1Department of Haematology, Oxford University Hospitals NHS Trust, Oxford, UK.
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.
Insights
Rapamycin targets the mammalian target of rapamycin (mTOR) pathway, but its efficacy in lymphoid malignancies is limited. Novel dual inhibitors targeting both mTORC1 and mTORC2 show promise for treating these cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The mammalian target of rapamycin (mTOR) pathway is crucial in cell signaling, proliferation, and tumor development.
- Rapamycin and its analogs primarily inhibit the mTORC1 complex, but show limited efficacy in lymphoid malignancies.
- Resistance mechanisms, including the discovery of mTORC2, necessitate new therapeutic strategies.
Purpose of the Study:
- To review the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mTOR pathway and rapamycin's action.
- To discuss rapamycin's clinical efficacy and resistance mechanisms in lymphoid cancers.
- To highlight the development and early data of novel dual mTOR inhibitors.
Main Methods:
- Literature review of the PI3K/AKT/mTOR pathway.
- Analysis of rapamycin's mechanism of action and clinical data in lymphoid malignancies.
- Examination of preclinical and early clinical data for dual mTOR inhibitors.
Main Results:
- First-generation mTOR inhibitors (rapamycin analogs) have shown limited success in lymphoid malignancies.
- mTORC2 is implicated in resistance to mTORC1 inhibitors.
- Novel dual inhibitors targeting both mTORC1 and mTORC2 are under investigation.
Conclusions:
- Targeting the mTOR pathway remains a key area in lymphoid malignancy treatment.
- Dual mTOR inhibitors represent a promising advancement over single-target inhibitors.
- Further clinical evaluation of dual mTOR inhibitors is warranted for lymphoid malignancies.