The mammalian target of rapamycin (mTOR) has emerged as a potential target for drug development particularly due to the fact that it plays such a crucial role in cancer biology. We will also discuss our recent comparative study of diferent mTOR inhibitors in a population of colon cancer stem cells (CSCs) and 4-O-Caffeoylquinic acid current major challenges for achieving individualized drug therapy using kinase inhibitors. oncogenicity in some cases. However the tumorigenic potential of the mTOR gene has only recently been established. By introducing mutations into evolutionarily conserved amino acid residues in major functional domains of human mTOR Murugan tumorigenicity. This discovery of oncogenic mTOR mutations may facilitate the design of drugs targeting mTOR as well as help predict their efficacy. For example in yeast resistance to Rapalogs has been associated with mutations in FK506 binding protein 12 (FKBP12) or the FKBP-rapamycin-binding (FRB) domain of TOR . mTOR’s role in proliferation differentiation and senescence While emerging evidence supports a central role of the mTOR pathway in cell growth and malignancy progression improved mTOR activity can also play a role mediating the depletion of the epithelial stem cell compartment. Indeed the aberrant activation of the mTOR pathway can paradoxically cause 4-O-Caffeoylquinic acid cells to undergo differentiation or senescence therefore exiting the proliferative cell pool . This concept is definitely well shown by the fact that prolonged activation of mTOR by wingless-related MMTV integration site 1 (Wnt1) prospects to accelerated epithelial stem cell senescence and 4-O-Caffeoylquinic acid premature ageing in mice [28 29 4-O-Caffeoylquinic acid Accordingly inhibition of mTOR helps prevent the loss of proliferative epithelial progenitor stem cells upon radiation and enhances their cells repopulating capacity . Similarly mTOR inhibition by Rapamycin enriches CD133+ subpopulations in liver tumor cells . This enrichment is most likely achieved through obstructing differentiation of the CD133+ subpopulations enhancing apoptosis in the CD133? subsets and triggering the conversion of CD133? to CD133+ cells. Therefore the maintenance of CD133+ cells by Rapamycin prospects to high continuous tumorigenic potential in the context of liver tumor. These data suggest that mTOR signaling is definitely involved in regulating the balance of 4-O-Caffeoylquinic acid proliferation and differentiation of malignancy stem cells (CSCs) and that transient inhibition of mTOR can promote tumor re-emergence in certain tumor types via enrichment of CSCs. The molecular mechanism(s) underlying these paradoxical effects of mTOR are not fully understood. It has been suggested that strong oncogenic signals (RAS PI3K) concomitantly induce cell cycle arrest and activation of growth-promoting (i.e. anabolic) pathways such mTOR. Cell cycle arrest by itself is not yet senescence . However in the presence of growth-stimulation cell cycle blockage eventually prospects to senescence. This mechanism by which arrested cells are converted to senescent cells has been named gerogenic conversion or geroconversion . To avoid geroconversion malignancy cells must shed manifestation of cell cycle inhibitors such as p53. Therefore cross-talk between p53 and the mTOR signaling pathways can determine whether stressed cells undergo apoptosis reversible quiescence or irreversible senescence . Inhibitors of mTOR can suppress geroconversion protecting adult stem cells from undergoing premature cell senescence while simultaneously avoiding their oncogenic transformation . Amongst mTOR inhibitors Rapamycin has been defined as a “longevity enhancer and malignancy preventative agent” in the context of p53 deficiency . Indeed continuous treatment with Rapamycin or a novel Rapamycin formulation (Rapatar) delayed carcinogenesis in tumor-prone p53+/?and p53?/?mice respectively most likely by slowing down the process of aging [37 38 Similarly chronic treatment of mice with an enterically released formulation of Rapamycin (eRapa) delayed the onset and/or progression of neuroendocrine NF2 tumors in Rb1+/? mice . Similarly hypoxia can decelerate geroconversion and lengthen life-span. Indeed not only does hypoxia arrests cell cycle but also inhibits the mTOR pathway therefore preventing irreversible cellular senescence . It turns out that in stem cell niches stem cells might be safeguarded from senescence and managed inside a quiescent status instead thanks to the low oxygen levels which characterize stem cell niches . Overall these studies point out molecular variations in normal and malignancy cells that can be.