mTOR Inhibitors: EVEROLIMUS, TEMSIROLIMUS
Mechanisms of Action
A. Reducing cell growth and proliferation
- Decreased cell cycle progression
- mTOR regulates protein synthesis of cyclin D1, which controls progression through the G1/S checkpoint → mTOR inhibition slows cell growth
- this may be particularly important in cancer cells characterized by overexpression of cyclin D1 (e.g., mantle cell lymphoma)
- mTOR regulates protein synthesis of cyclin D1, which controls progression through the G1/S checkpoint → mTOR inhibition slows cell growth
- Reduced bioenergetics
- cancer cells rely on glycolysis to provide ATP for sustained growth
- mTOR increases expression of amino acid and glucose transporters, which are upregulated in several cancers → mTOR inhibition decreases access to nutrient and metabolic fuel → decreased cell growth
B. Prevention of angiogenesis
- mTOR inhibitors prevent angiogenesis via two mechanisms
- decreasing synthesis and release of angiogenic growth factors (esp. VEGF and PDGF) from the cancer cells
- blocking growth and proliferation of vascular cells
C. Increased cytotoxicity of drugs that damage DNA
- DNA damage activates p53, which either triggers DNA repair or initiates cell death (if the DNA cannot be repaired)
- as part of this process, p53 controls transcription of the gene encoding p21, a cell cycle inhibitor that allows DNA repair to occur
- mTOR regulates translation of p21 → mTOR inhibition prevents p21-mediated cell cycle arrest → increasing the likelihood that the DNA-damaged cell will progress through the cell cycle, and die (remember the discussion of alkylating agents and p53)