Abstract
The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds.
Highlights
Rapamycin and RapalogsLiterature data have reported on first- and second-generation mammalian target of rapamycin (mTOR) inhibitors. Among the first generation inhibitors, rapamycin and its analogs, called rapalogs, are the most well studied drugs, and they are clinically used as cancer treatments
1. mammalian target of rapamycin (mTOR) Structure and Function mTOR is a 289-kDa serine/threonine kinase belonging to the phosphatidylinositol kinase-related kinase (PIKK) family
Its COOH-terminal catalytic domain shows a very high homology to the phosphoinositide 3-kinase (PI3K) [1]. mTOR is structurally associated with other proteins forming two functionally distinct complexes, mTOR complex 1 and mTOR complex 2, characterized by a different response to rapamycin and its derivatives [2,3]. mTORC1 includes mTOR, the regulatory-associated protein of mTOR (Raptor), the mammalian lethal with SEC13 protein 8, which stabilizes the kinase domain, and the following inhibitory components: DEP domain-containing mTOR-interacting protein (Deptor), PRAS40, and FKBP38 (FK506-binding protein 38). mTORC1 is sensitive to rapamycin and its derivatives (Figure 1)
Summary
Literature data have reported on first- and second-generation mTOR inhibitors. Among the first generation inhibitors, rapamycin and its analogs, called rapalogs, are the most well studied drugs, and they are clinically used as cancer treatments. Rapamycin (sirolimus) is a macrolide antibiotic that is produced by the microorganism Streptomyces hygroscopicus, which has been discovered in 1975 as a potent antifungal agent [84]. In following studies, it was associated with immunosuppression [85], which subsequently led to its development as a clinically useful drug in consideration of its anticancer activity [86]. Several studies have demonstrated that first generation inhibitors display limited anticancer activity, and that is partially due to the fact that the inhibition of mTORC1 by these drugs might lead to Akt upregulation and outgrowth of more aggressive lesions. Targeted strategies by combining rapamycin plus an inhibitor of Akt or PI3K, or the use of agents that target both PI3K and mTOR, or both mTORC1 and mTORC2, were developed to circumvent this loop [88]
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