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Cited by 268PI3K/AKT/mTOR signaling in cancerAdvanced Breast Cancer TherapiesMetabolism, Diabetes, and Cancer

The DOI matches its Crossref record; 83 of the 84 references it cites were found in a registry or an index.

mTOR inhibitors in cancer therapy

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Xie, Jianling, Wang, Xuemin, Proud, Christopher G.·2016·F1000Research
DOI 10.12688/f1000research.9207.1PMC PMC5007757
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Abstract

The mammalian target of rapamycin, mTOR, plays key roles in cell growth and proliferation, acting at the catalytic subunit of two protein kinase complexes: mTOR complexes 1 and 2 (mTORC1/2). mTORC1 signaling is switched on by several oncogenic signaling pathways and is accordingly hyperactive in the majority of cancers. Inhibiting mTORC1 signaling has therefore attracted great attention as an anti-cancer therapy. However, progress in using inhibitors of mTOR signaling as therapeutic agents in oncology has been limited by a number of factors, including the fact that the classic mTOR inhibitor, rapamycin, inhibits only some of the effects of mTOR; the existence of several feedback loops; and the crucial importance of mTOR in normal physiology.

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Figure 1. Schematic representation of signaling pathways involving the two mTOR complexes. Typically, hormones and growth factors activate mTOR complex 1 (mTORC1) through the SOS/Ras/Raf-MEK-ERK (MAPK) or the IRS1/PI3K-PDK1-PKB pathways or both. mTORC2 also contributes to the activation of PKB through the direct phosphorylation of its turn motif as well as its hydrophobic motif. These pathways impinge on the tuberous sclerosis complex (TSC), which serves as a GTPase activator protein for the small G-protein Rheb. Upon inhibitory phosphorylation evoked by upstream kinases such as PKB, the activity of TSC is suppressed, promoting the accumulation of GTP-bound Rheb, which in turn activates mTORC1 on the surface of lysosomes. Amino acids also activate mTORC1 by bringing the latter onto lysosomes via the Rag GTPases. S6K-rpS6 and 4EBP1-eIF4E are the best-characterized mTORC1 downstream targets and are responsible for controlling a variety of anabolic effects driven by mTORC1. Dashed lines indicate feedback mechanisms. mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.
Figure 1. Schematic representation of signaling pathways involving the two mTOR complexes. Typically, hormones and growth factors activate mTOR complex 1 (mTORC1) through the SOS/Ras/Raf-MEK-ERK (MAPK) or the IRS1/PI3K-PDK1-PKB pathways or both. mTORC2 also contributes to the activation of PKB through the direct phosphorylation of its turn motif as well as its hydrophobic motif. These pathways impinge on the tuberous sclerosis complex (TSC), which serves as a GTPase activator protein for the small G-protein Rheb. Upon inhibitory phosphorylation evoked by upstream kinases such as PKB, the activity of TSC is suppressed, promoting the accumulation of GTP-bound Rheb, which in turn activates mTORC1 on the surface of lysosomes. Amino acids also activate mTORC1 by bringing the latter onto lysosomes via the Rag GTPases. S6K-rpS6 and 4EBP1-eIF4E are the best-characterized mTORC1 downstream targets and are responsible for controlling a variety of anabolic effects driven by mTORC1. Dashed lines indicate feedback mechanisms. mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.CC BY · PubMed Central
Figure 2. Domains of the mTOR protein and three generations of mTOR inhibitors. mTOR is composed of 2,549 amino acids which can be divided into several structural domains, including HEAT (for anti-parallel α-helices found in Huntingtin, elongation factor 3, PP2 A and TOR1) repeats and FAT (for FRAP, ATM, TRAP), FRB, kinase, and FATC (for C-terminal FAT) domains. The HEAT repeats, located close to the N-terminus of mTOR, are required for mTOR multimerization. The FRB—FK506 binding protein 12 (FKBP12)–rapamycin binding—domain, as its name implies, is the binding site of mTOR to FKBP12 and rapamycin. FAT, kinase, and FATC domains are conserved within the phosphatidylinositol 3-kinase-related kinases (PIKKs) and are essential for maintaining the activity of PIKKs. The first-generation mTOR inhibitors, including rapamycin itself, bind to FKBP12, which in turn interacts with the FRB domain of mTOR to inhibit mTOR activity. The second-generation mTOR inhibitors are ATP-competitive mTOR inhibitors which act as ATP analogues and compete with ATP for the binding to the kinase domain of mTOR. The newly developed third generation of mTOR inhibitors can potentially overcome the drug resistance of cancer cells bearing mTOR FRB/kinase domain mutation; that is, FRB domain mutations (mTOR A2034V and mTOR F2108L) confer resistance to rapalogs (first generation), and a kinase domain mutation (mTOR M2327I) renders resistance to mTOR-KIs (second generation). mTOR, mammalian target of rapamycin.
Figure 2. Domains of the mTOR protein and three generations of mTOR inhibitors. mTOR is composed of 2,549 amino acids which can be divided into several structural domains, including HEAT (for anti-parallel α-helices found in Huntingtin, elongation factor 3, PP2 A and TOR1) repeats and FAT (for FRAP, ATM, TRAP), FRB, kinase, and FATC (for C-terminal FAT) domains. The HEAT repeats, located close to the N-terminus of mTOR, are required for mTOR multimerization. The FRB—FK506 binding protein 12 (FKBP12)–rapamycin binding—domain, as its name implies, is the binding site of mTOR to FKBP12 and rapamycin. FAT, kinase, and FATC domains are conserved within the phosphatidylinositol 3-kinase-related kinases (PIKKs) and are essential for maintaining the activity of PIKKs. The first-generation mTOR inhibitors, including rapamycin itself, bind to FKBP12, which in turn interacts with the FRB domain of mTOR to inhibit mTOR activity. The second-generation mTOR inhibitors are ATP-competitive mTOR inhibitors which act as ATP analogues and compete with ATP for the binding to the kinase domain of mTOR. The newly developed third generation of mTOR inhibitors can potentially overcome the drug resistance of cancer cells bearing mTOR FRB/kinase domain mutation; that is, FRB domain mutations (mTOR A2034V and mTOR F2108L) confer resistance to rapalogs (first generation), and a kinase domain mutation (mTOR M2327I) renders resistance to mTOR-KIs (second generation). mTOR, mammalian target of rapamycin.CC BY · PubMed Central
Figure 3. Selected examples of three generations of mTOR inhibitors and dual PI3K/mTOR inhibitors. Chemical structures were drawn by using the website www.emolecules.com. mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.
Figure 3. Selected examples of three generations of mTOR inhibitors and dual PI3K/mTOR inhibitors. Chemical structures were drawn by using the website www.emolecules.com. mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase.CC BY · PubMed Central

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Metadata

Authors
Xie, J., Wang, X., & Proud, C. G.
Affiliations
South Australian Health and Medical Research Institute (AU)
Corresponding author
Proud, Christopher G.
ORCID
Venue
F1000Research
Publisher
F1000 Research Ltd
Published
2016-08-25
Volume
5
Pages
2078
ISSN
2046-1402 (ISSN-L)
DOI
10.12688/f1000research.9207.1
PMC
PMC5007757
OpenAlex
W2517175971
Cited by
266
References
84
Citations by year
2026: 8 · 2025: 14 · 2024: 9 · 2023: 21 · 2022: 31 · 2021: 36 · 2020: 49 · 2019: 32 · 2018: 37 · 2017: 28 · 2016: 1
FWCI
2.96
Type
journal article
Language
en
Open access
Licence
Locations
  • F1000Research (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
mTOR inhibitors, mammalian target of rapamycin, mTORC1, mTORC2, rapamycin, cancer therapy, cell growth and proliferation, oncogenic signaling, feedback loops, drug resistance

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