593 POSTER Rational design of effective therapy combining irinotecan and rapamycin to target mTOR/HIF-1 alpha axis in colon cancer

Abstract

The mammalian target of rapamycin (mTOR) is a large multidomain protein whose function is inhibited by the immunosuppressant drug rapamycin. mTOR (or its homologues in lower eukaryotes) plays roles in cell growth and the cell cycle, control of the cytoskeleton and nutrient transport, protein and RNA stability and transcription and translation. In mammalian cells, the best understood effectors of mTOR are proteins involved in controlling the translational machinery. Signalling through mTOR is stimulated by amino acids and by hormones and mitogens. On the other hand, mTOR signaling is impaired in response to a range of stressful stimuli. These include DNA damage, nutrient withdrawal and depletion of cellular energy, as well as hypoxia. In response, e.g. to DNA damage, impairment of mTOR signaling appears to precede the commitment of cells to apoptosis. The mechanisms by which these stressful conditions still remain largely unclear. However, these responses make physiological sense, as impairment of mTOR signalling under these conditions will tend to inhibit anabolic processes and cell growth and division.