The Long Journey of mTOR Inhibitors and the Long Path That Is Still Ahead
This supplement summarizes recent data and provides critical analysis of the accumulated knowledge of the biological effects of mTOR inhibition. Zaza et al4 describe the effects of mTOR inhibition on protein synthesis, the cell cycle, lipid metabolism, energy metabolism, autophagy, angiogenesis, glucose metabolism, cytoskeleton remodeling, epithelial to mesenchymal transition, and immune cells development and function.
The use of mTOR inhibitors in different types of organ transplantation is also reviewed. Flechner provides a critical analysis of randomized clinical trials on different strategies of using mTOR inhibitors after kidney transplantation.5 Nashan6 summarizes data on liver transplants, with the focus on calcineurin inhibitor (CNI) minimization to preserve native renal function. Zuckermann7 discusses recent data on the use of mTOR inhibitors in heart transplantation, under CNI minimization and conversion strategies aiming to preserve renal function and to prevent the development of graft vasculopathy, CMV infection, and malignancy. Berney et al8 discuss both the beneficial and deleterious effects of mTOR inhibitors on β cells and how sirolimus and everolimus-based immunosuppression have impacted on practices and outcomes of pancreas and islet transplantation.
More general involvement of inhibition of the mTOR pathway in other diseases is also reviewed. Chan et al9 summarized the current understanding of mTOR signaling pathway under physiological and pathological conditions and recent findings on mTOR inhibitors in the management of kidney diseases. Vergès10 describes the deleterious and complex mechanisms by which mTOR inhibitors impair glucose metabolism by downregulation of the insulin signaling pathway, increasing the risk of diabetes in recipients of organ transplants or in patients with malignancies. De Meyer et al11 debated the net result of anti-atherosclerotic mTOR inhibitor effects versus the known dyslipidemia. Bowman et al12 highlight the role of mTORi in the management of viral infections after solid organ transplant, noting not only the potential role in the management of cytomegalovirus, poliomavirus, herpes virus 8, -related Kaposi sarcoma but also the lack of evidence for use of mTORis in EBV-mediated posttransplant lymphoproliferative disease or hepatitis C virus viral replication. Paoletti13 reviews data on mTOR associated regression of left ventricular hypertrophy in kidney transplant recipients with posttransplant cardiomyopathy. Finally, de Fijter14 details the effects of mTORi on malignancies, suggesting that observed clinical efficacy is a reflection of disease stabilization rather than tumor regression.
The efficacy of mTOR inhibitors in all its indications is limited by the complex safety and tolerability profile, the intricate aspects of which have begun to be uncovered using “omics.”15 Preclinical and clinical development of analogs, targeting different binding sites or producing selective inhibition of mTOR complexes (mTORC1 and mTORC2) may help improve the efficacy/toxicity profile of this class of drugs.