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. 2017 Jun 28;8(48):83570–83584. doi: 10.18632/oncotarget.18784

Figure 4. Schematic representation of the mechanisms of action for everolimus and trastuzumab.

Figure 4

Trastuzumab, a recombinant humanized monoclonal antibody, binds to the HER-2 (or c-erbB2) proto-oncogene, an extracellular domain of the human epidermal growth factor (EGF) receptor protein found on 20-30% of breast cancer cells. The binding leads to antibody-mediated killing of the HER2 positive cells. Trastuzumab inhibits the proliferation of human tumor cells that overexpress HER-2. It is a mediator of antibody dependent cellular cytotoxicity, in that the binding of the antibody to HER2 overexpressing cells leads to preferential cell death. Everolimus is a derivative of Rapamycin, and works similarly to Rapamycin as an mTOR (mammalian target of Rapamycin) inhibitor. Everolimus effect is solely on the mTORC1 protein, and not on mTORC2. Everolimus is a mTOR inhibitor that binds directly to a low-molecular-weight intracellular FKBP12 protein, thereby forming a drug complex that inhibits the activation of mTORC1. mTORC1 is a central regulator of protein synthesis, autophagy, mitochondrial function, lipogenesis, ketogenesis and glucose homeostasis in response to nutritional and environmental conditions. In a similar fashion to other mTOR inhibitors, the result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake. AKT: anaplastic lymphoma kinase; CAD: CAD trifunctional protein; EGF: epidermal growth factor; FKBP12: FK506-binding protein of 12 kDa; IRS-1 : insulin receptor substrate 1; MAPK : mitogen-activating protein kinase 1; MEK : mitogen-activated protein kinase ; mTOR: mammalian target of rapamycin; LARP1: la-related protein 1; Lipin1 : lipin-1 protein; PDK1 : 3-phosphoinositide dependent protein kinase-1; PI3K: phosphatidylinositol-4,5-biphosphate-3-kinase; PTEN : phosphatase and tensin homolog; RAS : ras protein ; RAF : raf protein kinase; Rheb : ras homolog enriched in brain; RSK1 : ribosomal s6 kinase 1; S6K1 : ribosomal protein S6 beta -1; SGK1 : serum and glucorticoid-regulated kinase 1; TFEB : tanscription factor EB; TSC : tuberous sclerosis complex ; ULK1: serine/threonine protein ULK1.