Mini-reviewmTOR inhibitors in cancer therapy
Introduction
The mammalian target of rapamycin (mTOR) is a highly conserved serine–threonine kinase belonging to the phosphatidylinositol kinase-related protein kinases family [1]. mTOR plays a central role in cellular homeostasis and has been implicated in a number of cellular events including cell growth, survival, and metabolism [2]. A growing body of evidence identifies activation of mTOR signaling as a common occurrence in human cancers [3]. Moreover, mTOR is closely intertwined with the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is strongly linked with neoplastic disease [2]. These factors have made mTOR an attractive option for the development of molecular targeted therapies, many of which have now progressed to clinical trials.
Section snippets
The mTOR signaling pathway
mTOR is a catalytic subunit composed of at least two distinct multi-protein complexes designated mTOR complex 1 (mTORC1) and mTORC2 [2] (Fig. 1). mTORC1 is comprised of mTOR, regulatory-associated protein of mTOR (Raptor), mLST8/GβL, Deptor, and proline-rich Akt substrate 40 [4]. mTORC1 is regulated by diverse environmental signals including nutrients, growth factors, energy signals, and cellular stress [1]. Additionally, the PI3K/Akt pathway is an important upstream mediator of mTORC1, which
The role of mTOR in cancer
In the last few years, significant advances have been made in understanding the role of mTOR in cancer development and progression. Increased mTOR signaling in cancers often occurs as a result of mutations in pathways closely related to mTOR. For example, upregulation of the PI3K/Akt pathway through mutations such as amplification of the PIK3CA gene (encodes the p110α subunit of PI3K) can constitutively activate mTOR signaling [23]. Furthermore, loss or inactivation of phosphatase and tensin
Rapamycin and its derivatives
Rapamycin (sirolimus), a naturally occurring compound isolated from the soil bacterium Streptomyces hydroscopius, was originally used as an antifungal and immunosuppressive agent [23]. Subsequent discovery of mTOR as the target of rapamycin and the drug’s inherent antiproliferative properties led to investigation of this compound as an anti-cancer agent. Limitations in the solubility and pharmacokinetic properties of rapamycin have driven efforts to improve upon these characteristics, resulting
ATP-competitive mTOR kinase inhibitors
Limitations of rapamycin-based therapies in the clinical setting have led to development of a second generation of mTOR inhibitors known as ATP-competitive mTOR kinase inhibitors (TKIs). These inhibitors target the kinase domain of mTOR and inhibit its catalytic activity. The mechanistic advantage of these drugs is that they inhibit the kinase activity of both the TORC1 and TORC2 complexes of mTOR, while also blocking the feedback activation of PI3K/Akt signaling [1], [49]. Numerous TKIs have
Dual mTOR/ PI3K inhibitors
The close interaction of mTOR with the PI3K pathway as well as concerns regarding resistance to TKIs via feedback activation of PI3K/Akt prompted development of dual PI3K/mTOR inhibitors. Recently developed dual PI3K/mTOR inhibitors include NVP-BEZ235, BGT226, XL765/SAR245409, SF1126, GDC-0980, PI-103, PF-04691502, PKI-587, and GSK2126458. These inhibitors target the p110α, β, and γ isoforms of PI3K as well as the ATP-binding sites of both mTORC1 and mTORC2, completely suppressing PI3K/Akt
Combinational strategies with mTOR inhibitors
Although a number of cancers respond to monotherapy treatment with rapalogs, TKIs, and dual PI3K/mTOR, resistance remains a major concern [43]. Combination therapeutic strategies may provide a way to overcome this resistance and improve efficacy of mTOR targeting agents. Rapalogs have been tested in combination with standard chemotherapy, receptor tyrosine kinase targeted therapies, and angiogenesis inhibitors [23]. For example, a recent study of epitheloid sarcoma demonstrated that the
Future perspectives
Given the limitations of currently available inhibitors, new approaches to mTOR targeting are under investigation. One possible strategy is to selectively inhibit mTORC2. Selective inhibition of mTORC2 would eliminate activation of PI3K through the S6K1-insulin receptor substrate 1 feedback loop [1]. Furthermore, the increased toxicity seen in TKIs as a result of concomitant mTORC1 inhibition may be avoided. Another potential strategy is to target DEP domain-containing mTOR-interacting protein
References (61)
- et al.
Mammalian target of rapamycin: discovery of rapamycin reveals a signaling pathway important for normal and cancer cell growth
Semin. Oncol.
(2009) - et al.
Regulation of eIF-4E BP1 phosphorylation by mTOR
J. Biol. Chem.
(1997) - et al.
MTOR and cancer: many loops in one pathway
Curr. Opin. Cell Biol.
(2010) - et al.
SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth
Cell Metab.
(2008) - et al.
An emerging role of mTOR in lipid biosynthesis
Curr. Biol.
(2009) - et al.
Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony
J. Biol. Chem.
(2010) - et al.
Activation of mTORC2 by association with the ribosome
Cell
(2011) - et al.
Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha but not S6K1
Dev. Cell
(2006) - et al.
Targeting the mTOR signaling network in cancer
Trends Mol. Med.
(2007) - et al.
RNA interference targeting raptor inhibits proliferation of gastric cancer cells
Exp. Cell Res.
(2011)
mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice
Cancer Cell
Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity
J. Biol. Chem.
mTOR mediated anti-cancer drug discovery
Drug Discov. Today Ther. Strateg.
Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML
Blood
Functional genomics identifies TOR-regulated genes that control growth and division
Curr. Biol.
Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients
J. Lipid Res.
DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival
Cell
MTOR: from growth signal integration to cancer, diabetes and ageing
Nat. Rev. Mol. Cell Biol.
MTOR signaling at a glance
J. Cell Sci.
Common corruption of the mTOR signaling network in human tumors
Oncogene
Raptor and mTOR: subunits of a nutrient-sensitive complex
Curr. Top Microbiol. Immunol.
United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling
Biochem. Soc. Trans.
Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation
Proc. Natl. Acad. Sci. USA
MTOR and cancer: insights into a complex relationship
Nat. Rev. Cancer
Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
J. Clin. Invest.
Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling
Science
The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling
Science
Transcriptional control of cellular metabolism by mTOR signaling
Cancer Res.
Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake
Mol. Biol Cell.
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Science
Cited by (250)
Protein Kinase Signaling Networks Driven by Oncogenic Gq/11 in Uveal Melanoma Identified by Phosphoproteomic and Bioinformatic Analyses
2023, Molecular and Cellular ProteomicsIntervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy
2023, North American Spine Society JournalmTOR signaling and autophagy regulation
2023, Autophagy Processes and MechanismsTherapeutic approaches for the treatment of head and neck squamous cell carcinoma–An update on clinical trials
2022, Translational OncologyRapamycin targets STAT3 and impacts c-Myc to suppress tumor growth
2022, Cell Chemical Biology