AFINITOR is a once-daily oral inhibitor of mTOR (mammalian target of rapamycin) for patients with advanced renal cell carcinoma (RCC) whose disease has progressed on or after treatment with VEGF-targeted therapy
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Cell Proliferation
Activation of mTOR leads to enhanced cell proliferation
A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of a protein (cyclin D1) which controls enzymes (cyclin-dependent kinases) that regulate the passage of cells through the critical G1-S restriction point of the cell cycle. Cyclin D1 has been shown to play a role in:1-3
- Gene transcription
- Cell metabolism
- Cell migration
In many cancers, mTOR is inappropriately "switched on" resulting in cyclin D1 overexpression, which has been associated with a number of cancers, including breast cancer, colon cancer, prostate cancer, lymphoma and melanoma.3
Activated mTOR may also play an additional role in cell cycle progression in cancer cells that have been treated with DNA-damaging agents, such as platinum drugs. Inhibiting mTOR has been shown to inhibit production of p21, the regulatory protein that stops the cell cycle. This increases the likelihood that damage caused by DNA-damaging agents will prove lethal to cancer cells.4
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References
1. Rosenwald IB, Kaspar R, Rousseau D, et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and posttranscriptional levels. J Biol Chem. 1995;270:21176-21180.
2. Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem. 2003;278:3656-3663.
3. Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: cyclin D1: normal and abnormal functions. Endocrinology. 2004;145:5439-5447.
4. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of P21 translation. Cell. 2005;120:747-759.
