Mtor inhibitors

Inhibitors for mTOR (mechanistic target of rapamcyin complex 1, a kinase) inhibit the transmission of the IL-2 signal (as do 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 unfold their effect at a later stage of lymphocyte activation. They inhibit the activity of protein kinases that are involved in signal transduction via the IL-2 receptor. This suppresses the proliferation of T cells. Furthermore, mTOR inhibitors prevent the occlusion of blood vessels in the graft by inhibiting the growth of endothelia. Note: Vascular occlusion is a relevant pathological mechanism in chronic graft rejection.

The 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 used with Sirolimus (=Rapamycin®, Rapamune®). Sirolimus is used among other things for the prophylaxis of an organ rejection after kidney transplantation.
• Everolimus: The Rapamycin analogue Everolimus (Certican®) is approved for the prophylaxis of transplant rejection after heart, kidney and liver transplantation.
• Two other preparations containing everolimus are 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 for example in renal angiomyolipoma (benign renal 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