Mtor inhibitors

Inhibitors for mTOR (mechanistic target of rapamcyin complex 1, a kinase) inhibit the transmission of IL-2 signaling (like calcineurin inhibitors, but via a different pathway). As a central cell pathway, the mTORC1 pathway controls cell growth, metabolism and autophagy. mTOR inhibitors are therefore kinase inhibitors.

Inhibitors for mTOR exert their effect at a later stage of lymphocyte activation. They inhibit the activity of protein kinases that are involved in signal transmission via the IL-2 receptor. This suppresses the proliferation of T cells. Furthermore, mTOR inhibitors prevent the occlusion of blood vessels in the transplant by inhibiting the growth of endothelia. Remark: Blood vessel occlusion is a relevant pathological mechanism in chronic transplant rejection.

mTOR kinase is important for many processes in the body, including a signaling pathway of the immune response. If the enzyme is inhibited, the immune system is specifically weakened.

• Sirolimus: This effect is utilized in the use of sirolimus (=Rapamycin®, Rapamune®). Sirolimus is used, among other things, to prevent organ rejection after kidney transplantation.
• Everolimus: The rapamycin analog everolimus (Certican®) is approved for the prophylaxis of transplant rejection after heart, kidney and liver transplantation.
• Two other preparations containing everolimus have been approved: Afinitor® and Votubia®. Afinitor is approved for the treatment of hormone receptor-positive advanced breast cancer, various neuroendocrine tumors and renal cell carcinoma.
• ^Votubia® can be used in subependymal giant cell astrocytoma (benign tumor of the brain), and e.g. in renal angiomyolipoma (benign kidney tumor).
• Temsirolimus: Another approved mTOR inhibitor is temsirolimus (Torisel®) with the indication: renal cell carcinoma and mantle cell lymphoma.

mTOR (acronym for mechanistic - also mammalian - Target of Rapamycin) is a protein found in all mammals to which the immunosuppressive drugs everolimus and rapamycin bind.

• mTOR is an enzyme important for cell survival, growth, proliferation and motility, which adds a phosphate group to several other proteins and enzymes and thus activates them. Thus mTOR is part of the signal transduction in the body and the beginning of a cascade of signalling pathways. mTOR is part of a protein complex that integrates different signalling pathways of growth factors, energy balance and oxygen concentration of the cell, regulates the production of proteins and thus controls cell growth and cell cycle. Blocking this enzyme leads to a global inhibition of the immune system.

1. Rangwala S et al (2011) Roles of the immune system in skin cancer. Br J Dermatol 165:953-965