Everolimus

Everolimus inhibits mammalian target of rapamycin (mTOR), a serine-threonine kinase acting downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, forming a complex that inhibits mTOR complex 1 (mTORC1) and thereby suppresses mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), both downstream effectors of mTOR involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor, resulting in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown, in in vitro and/or in vivo studies, to reduce cell proliferation, angiogenesis, and glucose uptake.

Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2-positive breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combining everolimus with Akt, HER2, or aromatase inhibitors enhances its anti-tumor activity in a synergistic manner.