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Review
. 2019 Feb 11;20(3):755.
doi: 10.3390/ijms20030755.

mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor _targeting Therapy

Tian Tian  1 , Xiaoyi Li  2 , Jinhua Zhang  3
Affiliations
Review

mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor _targeting Therapy

Tian Tian et al. Int J Mol Sci. .

Abstract

The mammalian or mechanistic _target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR _targeting drugs benefit the cancer patients in personalized therapy.

Keywords: PI3K; cancer; inhibitor; mTOR; therapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The mammalian or mechanistic _target of rapamycin (mTOR) complexes and signaling pathway of mTORC1 and mTORC2. mTORC1 is responsive to nutrients, hormones, amino acids, hypoxia and growth factors, while mTORC2 responds to growth factors. mTORC1 and mTORC2 share common subunits of mTOR kinase, mLST8, DEPTOR (DEP domain-containing mTOR-interacting protein), Tel 2 and Tti 1. mTORC1 additionally binds with RAPTOR (Regulatory-associated protein of mTOR) and PRAS40 (Proline-rich substrate of 40 kDa), and mTORC2 combines with RICTOR and mSIN1 (Mammalian stress-activated protein kinase interacting protein 1) as well as Protor and PRR5 (Proline-rich protein 5). mTORC1 is regulated by PI3K/Akt (Phosphoinositide 3-kinase/serine-threonine protein kinase) and Ras-MAPK (Mitogen activated protein kinase) signaling pathways. mTORC1 regulates protein translation and synthesis of nucleotide lipid via 4E-BP1 and S6K1 and downstream effectors. mTORC1 also activates STAT3 (Signal transducer and activator of transcription), HIF-1α (Hypoxia-inducible factor 1α) and PP2A (Protein phosphatase 2A) in tumorigenesis. mTORC2 regulates SGK (Serum glucose kinase) and PKC (Protein kinase C) to promote cell survival, cytoskeleton reorganization and cell migration. mTORC2 is negatively modulated by mTORC1 via different feedback loops mediated by IRS (insulin receptor substrate) or Grb10. mTORC1 and mTORC2 can both contribute to turmorigenesis through different mechanisms [7,11].
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