Abstract
The aim of this review was to summarize current available information about the role of phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling in cancer as a potential target for new therapy options. The mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) signaling are critical for the regulation of many fundamental cell processes including protein synthesis, cell growth, metabolism, survival, catabolism, and autophagy, and deregulated mTOR signaling is implicated in cancer, metabolic dysregulation, and the aging process. In this review, we summarize the information about the structure and function of the mTOR pathway and discuss the mechanisms of its deregulation in human cancers including genetic alterations of PI3K/AKT/mTOR pathway components. We also present recent data regarding the PI3K/AKT/mTOR inhibitors in clinical studies and the treatment of cancer, as well the attendant problems of resistance and adverse effects.
Highlights
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Like mTOR complex 1 (mTORC1), mTORC2 is formed by mammalian target of rapamycin (mTOR) and mammalian lethal with SEC13 protein 8 (mLST8) [14]. mTORC2 contains two essential specific components, rapamycin insensitive companion of mTOR (RICTOR) [15] and stress-activated map kinase-interacting protein 1 [16]; mTORC2 is associated with the facultative subunit protein observed with RICTOR (Protor)-1/2 [17]
The discovery of mTOR is a fundamental breakthrough in the understanding of cell growth, metabolism, and diseases
Summary
The activity of mTORC1 is regulated by amino acids, energy status, phosphatidic acid, and oxidative stress (reviewed in [72,73]). Amino acids stimulate the loading of RagA or RagB with GTP, which enables RagA/B to interact with the RAPTOR component of mTORC1 [77] This interaction results in the translocation of mTORC1 to the lysosomal surface, where the Rag GTPases dock on a multi-subunit complex called Ragulator, and lysosomal Rheb stimulates mTORC1 kinase activity [49]. Another important regulator of mTORC1 signaling is the AMP-activated protein kinase (AMPK), the principal energy sensor in most eukaryotic cells [78]. Regulatory mechanisms tightly control the activity and homeostasis of the PI3K/AKT/mTOR pathway, but it can be constitutively activated in various cancers. These mechanisms include the amplification or mutation of genes encoding PI3K subunits, AKT, and other pathway members; the activation of receptor tyrosine kinases, mutation, or overexpression of growth factor receptors, e.g., epithelial growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2); the inactivating mutations in the genes encoding key tumor suppressors PTEN or INPP4B; the inactivating mutations in the genes encoding mTOR regulators such as TSC1 and TSC2; and the activating mutations in MTOR itself [91,92,93]
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