New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

Abstract

The macrolide rapamycin and its analogues (rapalogs) constitute the first generation of mammalian target of rapamycin (mTOR) inhibitors. Since the introduction of rapamycin as an immunosuppressant, there has been extensive progress in understanding its complex mechanisms of action. New insights into the function of mTOR in different immune cell types, vascular endothelial cells and neoplastic cells have opened new opportunities and challenges regarding mTOR as a pharmacological target. Currently, the two known mTOR complexes, mTOR complex (mTORC) 1 and mTORC2, are the subject of intense investigation, and the introduction of second-generation dual mTORC kinase inhibitors (TORKinibs) and gene knockout mice is helping to uncover the distinct roles of these complexes in different cell types. While the pharmacological profiling of rapalogs is advanced, much less is known about the properties of TORKinibs. A potential benefit of mTOR inhibition in transplantation is improved protection against transplant-associated viral infections compared with standard calcineurin inhibitor-based immunosuppression. Preclinical and clinical data also underscore the potentially favourable antitumour effects of mTOR inhibitors in regard to transplant-associated malignancies and as a novel treatment option for various other cancers. Many aspects of the mechanisms of action of mTOR inhibitors and their clinical implications remain unknown. In this brief review we discuss new findings and perspectives of mTOR inhibitors in transplantation.

Keywords: Raptor; Rictor; immune cells; mammalian target of rapamycin; transplantation.

Figure 1

The mammalian target of rapamycin (mTOR) complexes. mTOR complex (mTORC) 1 is formed by mTOR, mammalian lethal with SEC13 protein 8 (mLST8), proline‐rich Akt substrate of 40 kDa (PRAS40), Dep domain‐containing mTOR‐interacting protein (Deptor) and the regulatory associated protein of mTOR (Raptor). Cytokines, growth factors, various nutritional cues and Akt influence the activity of tuberous sclerosis complex (TSC) 1 and TSC2, which control the activity of the GTPase RAS homologue enriched in the brain (RHEB). The interaction with RHEB is followed by phosphorylation of mTOR and leads to mRNA translation by stimulating s6 kinase 1 (S6K1) and phosphorylating eukaryotic translation initiation factor‐binding protein 1 (4E‐BP1), dissociating the inhibitory effect of 4E‐BP1 on eIF4E, a cap‐dependent mRNA translation, in mTORC1 signalling. The activation of S6k1 leads to a negative feedback loop over the phosphatidylinositol 3‐kinase (PI3K)–Akt axis via insulin receptor substrate. mTORC2 is formed by the additional components protein observed with Rictor (Protor) 1/2 and stress‐activated protein kinase‐interacting protein 1 (Sin 1). It is activated by PI3K and is only partially inhibited by rapamycin. Activation of mTORC2 regulates cytoskeletal changes via small GTPase Ras homologue (Rho) and protein kinase Cα (PKCα). Activation of serum‐ and glucocorticoid‐induced protein kinase 1 (SGK1) by mTORC2 regulates the epithelial Na⁺ channel in kidneys. mTORC2 phosphorylates Akt and can influence the activity of TSC1/2. MAPK, mitogen‐activated protein kinase