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

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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.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.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.CC BY · PubMed Central

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Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · cited 6×
“DI, dual mammalian target of rapamycin/phosphoinositide 3-kinase inhibitor; HCC, hepatocellular carcinoma; MBC, metastatic breast cancer; mTOR, mammalian target of rapamycin; NSCLC, non-small cell lung cancer; PI3K, phosphoinositide 3-kinase; pNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma. shows effe…”
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Shapiro, A. M. J., Lakey, J. R. T., Ryan, E. A., Korbutt, G. S., Toth, E., Warnock, G. L., Kneteman, N. M., & Rajotte, R. V. (2000) · New England Journal of Medicine · doi:10.1056/nejm200007273430401 · Cited by 5,237
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · cited 2×
“DI XL765 Phase I/II (5) Sanofi-Aventis, Exelixis Glioblastoma multiforme/NSCLC/ MBC 39”
Background
Otto Warburg's contributions to current concepts of cancer metabolism
Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3038 · Cited by 3,427
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365 · cited 3×
“Although rapamycin is a highly selective inhibitor against mTOR, it does not completely inhibit all of the activities of mTORC1 28 and will inhibit mTORC2 in only some types of cells upon prolonged treatment 29 .”
BackgroundInfluential
COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer
Forbes, S. A., Bindal, N., Bamford, S., Cole, C., Kok, C. Y., Beare, D., Jia, M., Shepherd, R., Leung, K., Menzies, A., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq929 · Cited by 2,278 · cited 1×
“Given the many oncogenic pathways—and oncogenes or tumor suppressors—linked to mTOR signaling, it is estimated that mTORC1 function is hyperactivated in up to 70% of all human tumors 18 .”
Background
MTOR: a pharmacologic target for autophagy regulation
Kim, Y. C., & Guan, K.-L. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73939 · Cited by 2,126 · cited 1×
“DI GSK2126458 Phase I/II (3) GlaxoSmithKline Advanced solid tumors, lymphoma 38”
Background
An ATP-competitive Mammalian Target of Rapamycin Inhibitor Reveals Rapamycin-resistant Functions of mTORC1
Thoreen, C. C., Kang, S. A., Chang, J. W., Liu, Q., Zhang, J., Gao, Y., Reichling, L. J., Sim, T., Sabatini, D. M., & Gray, N. S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m900301200 · Cited by 1,803
Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle.
Vézina, C., KUDELSKI, A., & Sehgal, S. N. (1975) · The Journal of Antibiotics · doi:10.7164/antibiotics.28.721 · Cited by 1,691
Five-Year Follow-Up After Clinical Islet Transplantation
Ryan, E. A., Paty, B. W., Senior, P. A., Bigam, D., Alfadhli, E., Kneteman, N. M., Lakey, J. R. T., & Shapiro, A. M. J. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2060 · Cited by 1,641 · cited 1×
“…islet transplantations 52 , yet a follow-up study 5 years later has demonstrated that only approximately 10% of the recipients remained insulin independent 53 , likely owing to the fact that mTOR inhibitors would induce pancreatic β -cell death 54,55 as a result of the inhibition of mTORC2 56 .”
Background
Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers
Engelman, J. A., Chen, L., Tan, X., Crosby, K., Guimaraes, A. R., Upadhyay, R., Maira, M., McNamara, K., Perera, S. A., Song, Y., et al. (2008) · Nature Medicine · doi:10.1038/nm.1890 · Cited by 1,330 · cited 1×
“Not only does the dual mTOR/PI3K inhibitor NVP-BEZ235 exert potent anti-tumor activity in vivo but its effect can be further enhanced by the combination with inhibitors against other mitogenic pathways, such as the MEK/ERK inhibitors 36,37 .”
Background
The translational landscape of mTOR signalling steers cancer initiation and metastasis
Hsieh, A. C., Liu, Y., Edlind, M. P., Ingolia, N. T., Janes, M. R., Sher, A., Shi, E. Y., Stumpf, C. R., Christensen, C., Bonham, M. J., et al. (2012) · Nature · doi:10.1038/nature10912 · Cited by 1,313 · cited 1×
“INK128 (later renamed MLN0128) is a PP242 derivative developed by Intellikine 44 and has been, or is being, tested in 25 clinical trials, according to ClinicalTrials.gov (Table 1).”
Rapamycin: one drug, many effects
Li, J., Kim, S. G., & Blenis, J. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.01.001 · Cited by 1,287 · cited 2×
“26 .”
Background
Akt signalling in health and disease
Hers, I., Vincent, E. E., & Tavaré, J. M. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.05.004 · Cited by 1,268 · cited 1×
“…the production of ribosomes 9,10 . mTORC2 has distinct substrates from mTORC1 11 , which include AKT (PKB) 12 , a protein kinase that is involved in anabolic signaling (for example, in the activation of mTORC1 13–15 and in cell survival 16 ), and SGK1, whose function is rather less well understood.”
Background
Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity
Maira, S.-M., Stauffer, F., Brueggen, J., Furet, P., Schnell, C., Fritsch, C., Brachmann, S., Chène, P., De Pover, A., Schoemaker, K., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0017 · Cited by 1,134
Active-Site Inhibitors of mTOR Target Rapamycin-Resistant Outputs of mTORC1 and mTORC2
Feldman, M. E., Apsel, B., Uotila, A., Loewith, R., Knight, Z. A., Ruggero, D., & Shokat, K. M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000038 · Cited by 1,111 · cited 4×
“As a classic indication of complete mTORC1 inhibition, the phosphorylation of the rapamycin-resistant sites in 4E-BP1 (Thr37/Thr46) is effectively blocked by PP242 42 .”
BackgroundInfluential
Making new contacts: the mTOR network in metabolism and signalling crosstalk
Shimobayashi, M., & Hall, M. N. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3757 · Cited by 1,053 · cited 1×
“Each plays key roles in cellular regulation 1,2 . mTORC1 drives multiple anabolic pathways, including protein synthesis, ribosome production, lipogenesis, and nucleotide synthesis, all of which are important for cell and tissue growth 1 . mTORC1 also suppresses a key catabolic process, autophagy 3…”
Background
Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization.
Sehgal, S. N., BAKER, H., & Vézina, C. (1975) · The Journal of Antibiotics · doi:10.7164/antibiotics.28.727 · Cited by 974
Amino acid signalling upstream of mTOR
Jewell, J. L., Russell, R. C., & Guan, K.-L. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3522 · Cited by 894 · cited 1×
“…activities or subcellular localization 3 . mTORC1 signaling is activated by several oncogenic pathways, including the Ras/Raf/MEK/ ERK pathway and the phosphoinositide 3-kinase (PI3K)/AKT (PKB) pathway (Figure 1), and by the intracellular availability of energy (ATP) and essential amino acids 4,5 .”
Background
Tuberous sclerosis complex
Henske, E. P., Jóźwiak, S., Kingswood, J. C., Sampson, J. R., & Thiele, E. A. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.35 · Cited by 886
Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin
Brunn, G. J., Hudson, C. C., Sekulić, A., Williams, J. M., Hosoi, H., Houghton, P. J., Lawrence, J. C., & Abraham, R. T. (1997) · Science · doi:10.1126/science.277.5322.99 · Cited by 846 · cited 2×
“They are phosphorylated by mTORC1 and this induces their release from eIF4E, thereby alleviating such inhibition 7 .”
Background
Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation
Choo, A. Y., Yoon, S.-O., Kim, S. G., Roux, P. P., & Blenis, J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0809136105 · Cited by 829 · cited 1×
“The data suggest that its effect on mTORC1 activity affects mainly weaker mTORC1 substrates, such as the protein kinase termed ribosomal protein rpS6 kinase, whereas it has only a limited, if any, effect on other, better substrates such as the eIF4E-binding protein 4E-BP1 19 .”
Background
AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity
Chresta, C. M., Davies, B. R., Hickson, I., Harding, T., Cosulich, S., Critchlow, S. E., Vincent, J. P., Ellston, R., Jones, D., Sini, P., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-1751 · Cited by 812 · cited 1×
“Indeed, AZD8055 is shown to activate autophagic flux in a variety of cancer cells 50,57,58 and the inhibition of autophagy was able to reverse the paradoxical cytoprotective effect of AZD8055 on colon carcinoma cells 57 .”
Background
Drosophila S6 kinase: a regulator of cell size.
Montagne, J., Stewart, M. J., Stocker, H., Hafen, E., Kozma, S., & Thomas, G. (1999) · Science · doi:10.1126/science.285.5436.2126 · Cited by 785
mTORC1-Mediated Cell Proliferation, But Not Cell Growth, Controlled by the 4E-BPs
Dowling, R. J. O., Topisirović, I., Alain, T., Bidinosti, M., Fonseca, B. D., Petroulakis, E., Wang, X., Larsson, O. S., Selvaraj, A., Liu, Y., et al. (2010) · Science · doi:10.1126/science.1187532 · Cited by 733 · cited 1×
“4E-BP1 is the substrate through which mTORC1 controls cell proliferation 23 , so the resistance of its phosphorylation to rapamycin likely contributes to the poor efficiency of rapamycin as an anti-hyperplastic agent.”
Background
Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
Shima, H., Pende, M., Chen, Y., Fumagalli, S., THOMAS, G. V., & Kozma, S. C. (1998) · The EMBO Journal · doi:10.1093/emboj/17.22.6649 · Cited by 636
Small-Molecule Inhibition of the Interaction between the Translation Initiation Factors eIF4E and eIF4G
Moerke, N. J., Aktaş, H., Chen, H., Cantel, S., Reibarkh, M., Fahmy, A., Gross, J. D., Degterev, A., Yuan, J., Chorev, M., et al. (2007) · Cell · doi:10.1016/j.cell.2006.11.046 · Cited by 580 · cited 1×
“Alternative ways of impairing eIF4E function may be effective in such settings; possibilities include the use of anti-sense RNAs against its mRNA 61 , and blocking its binding to its partner eIF4G 62 .”
Background
Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53
Bywater, M. J., Poortinga, G., Sanij, E., Hein, N., Peck, A., Cullinane, C. M., Wall, M., Cluse, L. A., Drygin, D., Anderes, K. L., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.05.019 · Cited by 561 · cited 1×
“Bywater et al . have developed an inhibitor of Pol I, CX-5461 70 , which, when used in combination with everolimus, extended the survival of mice with myc-driven lymphoma 71 .”
Method
The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging
Kennedy, B. K., & Lamming, D. W. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.009 · Cited by 544 · cited 1×
“2nd OSI027 Phase I/II (1) OSI Pharmaceuticals Advanced solid tumors/lymphoma 82”
Background
SDZ RAD, A NEW RAPAMYCIN DERIVATIVE
Schüler, W., Sedrani, R. C., Cottens, S., berlin, B. H., Schulz, M., Schuurman, H., Zenke, G., Zerwes, H., & Schreier, M. H. (1997) · Transplantation · doi:10.1097/00007890-199707150-00008 · Cited by 534 · cited 1×
“For example, RAD001 (everolimus) 32,33 , developed by Novartis as an immuno-suppressive and anti-cancer drug (Table 1), is a hydroxyethyl ether-derivative.”
Background
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Hannan, K. M., Brandenburger, Y., Jenkins, A., Sharkey, K., Cavanaugh, A. H., Rothblum, L. I., Moss, T., Poortinga, G., McArthur, G. A., Pearson, R. B., et al. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.23.8862-8877.2003 · Cited by 489 · cited 1×
“This almost certainly reflects a role for S6K1 in controlling ribosome biogenesis 67,68 , a key process for cell growth control, although additional events may also be involved.”
Background
Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor
Rodrik-Outmezguine, V. S., Okaniwa, M., Yao, Z., Novotny, C. J., McWhirter, C., Banaji, A., Won, H., Wong, W., Berger, M., de Stanchina, E., et al. (2016) · Nature · doi:10.1038/nature17963 · Cited by 479
Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)
García‐Martínez, J. M., Moran, J., Clarke, R. G., Gray, A., Cosulich, S. C., Chresta, C. M., & Alessi, D. R. (2009) · Biochemical Journal · doi:10.1042/bj20090489 · Cited by 473 · cited 1×
“Ku-0063794 and Ku-0068650 47,48 , developed by KuDOS Pharmaceuticals (now part of AstraZeneca), are also examples of early ATP-competitive mTOR inhibitors which exhibit great anti-proliferative potential against cancer cells in vitro .”
Background
A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity
Grabiner, B. C., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A. C., Beck, A. H., & Sabatini, D. M. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0929 · Cited by 470
Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases
Apsel, B., Blair, J. A., González, B., Nazif, T. M., Feldman, M. E., Aizenstein, B., Hoffman, R., Williams, R. L., Shokat, K. M., & Knight, Z. A. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.117 · Cited by 460 · cited 4×
“As a classic indication of complete mTORC1 inhibition, the phosphorylation of the rapamycin-resistant sites in 4E-BP1 (Thr37/Thr46) is effectively blocked by PP242 42 .”
BackgroundInfluential
mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling
Julien, L.-A., Carriere, A., Moreau, J., & Roux, P. P. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00601-09 · Cited by 452 · cited 1×
“Also, S6K can phosphorylate Rictor and thereby impair mTORC2 function, an effect that should be reversed by rapamycin 30,31 .”
Background
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Rodrik-Outmezguine, V. S., Chandarlapaty, S., Pagano, N. C., Poulikakos, P. I., Scaltriti, M., Moskatel, E., Baselga, J., Guichard, S., & Rosen, N. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0085 · Cited by 442 · cited 1×
“2nd INK128/MLN0128 Phase I/II (25) Intellikine Advanced solid tumors/multiple myeloma/Waldenstrom macroglobulinemia 44”
Background
Genetic Dissection of the Oncogenic mTOR Pathway Reveals Druggable Addiction to Translational Control via 4EBP-eIF4E
Hsieh, A. C., Costa, M., Zollo, O., Davis, C., Feldman, M. E., Testa, J. R., Meyuhas, O., Shokat, K. M., & Ruggero, D. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.021 · Cited by 434
Dynamic Adipocyte Phosphoproteome Reveals that Akt Directly Regulates mTORC2
Humphrey, S. J., Yang, G., Yang, P., Fazakerley, D. J., Stöckli, J., Yang, J. Y. H., & James, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.010 · Cited by 412 · cited 1×
“…the production of ribosomes 9,10 . mTORC2 has distinct substrates from mTORC1 11 , which include AKT (PKB) 12 , a protein kinase that is involved in anabolic signaling (for example, in the activation of mTORC1 13–15 and in cell survival 16 ), and SGK1, whose function is rather less well understood.”
Background
Regulation and function of the RSK family of protein kinases
Roméo, Y., Zhang, X., & Roux, P. P. (2011) · Biochemical Journal · doi:10.1042/bj20110289 · Cited by 392
Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin
Knight, S. D., Adams, N. D., Burgess, J. L., Chaudhari, A. M., Darcy, M. G., Donatelli, C. A., Luengo, J. I., Newlander, K. A., Parrish, C. A., Ridgers, L. H., et al. (2010) · ACS Medicinal Chemistry Letters · doi:10.1021/ml900028r · Cited by 378 · cited 1×
“Other examples from this class of inhibitors include GSK2126458 from GlaxoSmithKline 38 , XL765 from Sanofi-Aventis and Exelixis 39 , and SF1126 from Semafore 40 .”
Background
Structure of the Human mTOR Complex I and Its Implications for Rapamycin Inhibition
Yip, C. K., Murata, K., Walz, T., Sabatini, D. M., & Kang, S. A. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.017 · Cited by 372 · cited 1×
“20 , which showed that rapamycin treatment results in destabilization of the hollow lozenge-shaped mTORC1 dimer, a recent high-resolution cryo-electron microscopy study from Aylett et al .”
Background
Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin
Yu, K., Toral‐Barza, L., Shi, C., Zhang, W., Lucas, J., Shor, B., Kim, J., Verheijen, J. C., Curran, K. J., Malwitz, D. J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-0299 · Cited by 344 · cited 1×
“Wyeth-Ayerst (now part of Pfizer) developed a series of dual mTORC1/2 inhibitors via high-throughput screening based on the parent compound WAY-001 and subsequently named them WAY-600, WYE-687, and WYE-354 49 .”
Background
Architecture of human mTOR complex 1
Aylett, C. H. S., Sauer, E., Imseng, S., Boehringer, D., Hall, M. N., Ban, N., & Maier, T. (2016) · Science · doi:10.1126/science.aaa3870 · Cited by 344 · cited 1×
“21 showed that the binding of rapamycin-FKBP12 to mTOR does not destabilize the mTORC1 dimer but rather reduces the access to the active site cleft from a width of 20 to 10 Å, implying that the FKBP12-rapamycin binding (FRB) domain acts as a gatekeeper of the active substrate binding site…”
Background
Ribosomal protein S6 kinase activity controls the ribosome biogenesis transcriptional program
Chauvin, C., Koka, V., Nouschi, A., Mieulet, V., Hoareau‐Aveilla, C., Dreazen, A., Cagnard, N., Carpentier, W., Kiss, T., Meyuhas, O., et al. (2013) · Oncogene · doi:10.1038/onc.2012.606 · Cited by 310
A Positive Feedback Loop between Akt and mTORC2 via SIN1 Phosphorylation
Yang, G., Murashige, D., Humphrey, S. J., & James, D. E. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.016 · Cited by 297 · cited 1×
“…the production of ribosomes 9,10 . mTORC2 has distinct substrates from mTORC1 11 , which include AKT (PKB) 12 , a protein kinase that is involved in anabolic signaling (for example, in the activation of mTORC1 13–15 and in cell survival 16 ), and SGK1, whose function is rather less well understood.”
Background
Activating mTOR Mutations in a Patient with an Extraordinary Response on a Phase I Trial of Everolimus and Pazopanib
Wagle, N., Grabiner, B. C., Allen, E. M. V., Hodis, E., Jacobus, S. J., Supko, J. G., Stewart, M. L., Choueiri, T. K., Gandhi, L., Cleary, J. M., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0353 · Cited by 282 · cited 2×
“A final issue compromising the efficacy of mTOR inhibitors is that a wide range 72–76 of clinically relevant mutations in mTOR can increase the catalytic activity of mTOR and thus both mTORC1 and mTORC2, thereby reducing the effectiveness of such compounds toward the first two generations of mTOR…”
Background
A Vascular Targeted Pan Phosphoinositide 3-Kinase Inhibitor Prodrug, SF1126, with Antitumor and Antiangiogenic Activity
Garlich, J. R., De, P. K. R., Dey, N., Su, J. D., Peng, X., Miller, A., Murali, R., Lu, Y., Mills, G. B., Kundra, V., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-0669 · Cited by 280 · cited 1×
“Other examples from this class of inhibitors include GSK2126458 from GlaxoSmithKline 38 , XL765 from Sanofi-Aventis and Exelixis 39 , and SF1126 from Semafore 40 .”
Background
Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941
Raynaud, F. I., Eccles, S. A., Patel, S. K., Alix, S., Box, G., Chuckowree, I., Folkes, A. J., Gowan, S. M., Brandon, A. D. H., Stefano, F. D., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-1200 · Cited by 273 · cited 1×
“The first inhibitors that came out from this group of compounds were PI103 and its derivatives, named PI450 and PI620, which show further improvements to the pharmacokinetic properties of the parent molecule 34 .”
Background
Rapamycin inhibits mTORC1, but not completely
Thoreen, C. C., & Sabatini, D. M. (2009) · Autophagy · doi:10.4161/auto.5.5.8504 · Cited by 268
Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
Geoerger, B., Kerr, K., Tang, C. B., Fung, K., Powell, B., Sutton, L. N., Phillips∥, P. C., & Janss, A. J. (2001) · PubMed · Cited by 261
mTORC1 signaling controls multiple steps in ribosome biogenesis
Iadevaia, V., Liu, R., & Proud, C. G. (2014) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2014.08.004 · Cited by 248
SDZ RAD, A NEW RAPAMYCIN DERIVATIVE
Schuurman, H., Cottens, S., Fuchs, S., Joergensen, J., Meerloo, T., Sedrani, R. C., Tanner, M., Zenke, G., & Schüler, W. (1997) · Transplantation · doi:10.1097/00007890-199707150-00007 · Cited by 248 · cited 1×
“For example, RAD001 (everolimus) 32,33 , developed by Novartis as an immuno-suppressive and anti-cancer drug (Table 1), is a hydroxyethyl ether-derivative.”
Background
Signalling to eIF4E in cancer
Siddiqui, N., & Sonenberg, N. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150126 · Cited by 225
Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer
Sato, T., Nakashima, A., Guo, L., Coffman, K., & Tamanoi, F. (2010) · Oncogene · doi:10.1038/onc.2010.28 · Cited by 223
Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR
Liu, Q., Xu, C., Kirubakaran, S., Zhang, X., Hur, W., Liu, Y., Kwiatkowski, N. P., Wang, J., Westover, K. D., Gao, P., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-1702 · Cited by 219
Optimization of potent and selective dual mTORC1 and mTORC2 inhibitors: The discovery of AZD8055 and AZD2014
Pike, K. G., Malagu, K., Hummersone, M., Menear, K. A., Duggan, H. M. E., Gomez, S., Martin, N. M. B., Ruston, L., Pass, S. L., & Pass, M. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.01.019 · Cited by 214 · cited 1×
“Moreover, AZD8055 and AZD2014 50,51 are two orally bioavailable compounds derived from the Ku compounds.”
Background
Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells
Carayol, N., Vakana, E., Sassano, A., Kaur, S., Goussetis, D. J., Glaser, H., Druker, B. J., Donato, N. J., Altman, J. K., Barr, S. M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1005114107 · Cited by 179
The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia
Willems, L., Chapuis, N., Puissant, A., Maciel, T. T., Green, A. S., Jacque, N., Vignon, C., Park, S., Guichard, S. M., Hérault, O., et al. (2011) · Leukemia · doi:10.1038/leu.2011.339 · Cited by 172
Rapamycin (AY-22,989), a new antifungal antibiotic. III. In vitro and in vivo evaluation.
BAKER, H., SIDOROWICZ, A., Sehgal, S. N., & Vézina, C. (1978) · The Journal of Antibiotics · doi:10.7164/antibiotics.31.539 · Cited by 168
Rapamycin Has a Deleterious Effect on MIN-6 Cells and Rat and Human Islets
Bell, E., Cao, X., Moibi, J. A., Greene, S. R., Young, R., Trucco, M. M., Gao, Z., Matschinsky, F. M., Deng, S., Markman, J. F., et al. (2003) · Diabetes · doi:10.2337/diabetes.52.11.2731 · Cited by 165
eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies
Alain, T., Morita, M., Fonseca, B. D., Yanagiya, A., Siddiqui, N., Bhat, M., Zammit, D., Marcus, V., Metrakos, P. P., Voyer, L.-A., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-2395 · Cited by 165 · cited 1×
“One of the key targets for control by mTORC1, eIF4E, is often expressed at high levels in tumors 8 ; if its levels exceed those of its mTORC1-regulated inhibitors, 4E-BPs, then inhibition of mTORC1 will not be effective in restricting eIF4E function 60 .”
Background
TORC2 Structure and Function
Gaubitz, C., Prouteau, M., Kuśmider, B., & Loewith, R. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.04.001 · Cited by 163 · cited 1×
“…other links from mTORC1 to the activation of protein synthesis and to the production of ribosomes 9,10 . mTORC2 has distinct substrates from mTORC1 11 , which include AKT (PKB) 12 , a protein kinase that is involved in anabolic signaling (for example, in the activation of mTORC1 13–15 and in cell…”
Background
Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function
Zhang, N., Su, D., Qu, S., Tse, T. E., Bottino, R., Balamurugan, A. N., Xu, J., Bromberg, J. S., & Dong, H. H. (2006) · Diabetes · doi:10.2337/db06-0173 · Cited by 158
mTORC1 signalling and mRNA translation
Proud, C. G. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370227 · Cited by 133 · cited 1×
“There are two genes in mammals, often termed S6K1 and S6K2 , each of which gives rise to two protein isoforms 63 .”
Background
Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma
Devlin, J. R., Hannan, K. M., Hein, N., Cullinane, C. M., Kusnadi, E. P., Ng, P. Y., George, A. J., Shortt, J., Bywater, M. J., Poortinga, G., et al. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0673 · Cited by 126 · cited 1×
“Bywater et al . have developed an inhibitor of Pol I, CX-5461 70 , which, when used in combination with everolimus, extended the survival of mice with myc-driven lymphoma 71 .”
Method
Eukaryotic elongation factor 2 kinase as a drug target in cancer, and in cardiovascular and neurodegenerative diseases
Liu, R., & Proud, C. G. (2016) · Acta Pharmacologica Sinica · doi:10.1038/aps.2015.123 · Cited by 117 · cited 1×
“Inhibition of mTORC1 will also activate its downstream effector, eukaryotic elongation factor 2 kinase (eEF2K), which can promote cell survival 27 .”
Background
Rapamycin (AY-22,989), a new antifungal antibiotic. IV. Mechanism of action.
Singh, K., Sun, S., & Vézina, C. (1979) · The Journal of Antibiotics · doi:10.7164/antibiotics.32.630 · Cited by 95
Inhibition of mTOR Kinase by AZD8055 Can Antagonize Chemotherapy-induced Cell Death through Autophagy Induction and Down-regulation of p62/Sequestosome 1
Huang, S., Yang, Z. J., Yu, C., & Sinicrope, F. A. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.297432 · Cited by 93 · cited 1×
“Indeed, AZD8055 is shown to activate autophagic flux in a variety of cancer cells 50,57,58 and the inhibition of autophagy was able to reverse the paradoxical cytoprotective effect of AZD8055 on colon carcinoma cells 57 .”
Background
Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis
Iadevaia, V., Huo, Y., Zhang, Z., Foster, L. J., & Proud, C. G. (2012) · Biochemical Society Transactions · doi:10.1042/bst20110682 · Cited by 93
Characterization of the Activity of the PI3K/mTOR Inhibitor XL765 (SAR245409) in Tumor Models with Diverse Genetic Alterations Affecting the PI3K Pathway
Yu, P., Laird, A., Du, X., Wu, J., Won, K., Yamaguchi, T., Hsu, P. P., Qian, F., Jaeger, C. T., Zhang, W., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0709 · Cited by 82 · cited 1×
“Other examples from this class of inhibitors include GSK2126458 from GlaxoSmithKline 38 , XL765 from Sanofi-Aventis and Exelixis 39 , and SF1126 from Semafore 40 .”
Background
The discovery and optimisation of pyrido[2,3-d]pyrimidine-2,4-diamines as potent and selective inhibitors of mTOR kinase
Malagu, K., Duggan, H. M. E., Menear, K. A., Hummersone, M., Gomez, S., Bailey, C., Edwards, P., Drzewiecki, J., Leroux, F. R., Quesada, M. J., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.08.038 · Cited by 81 · cited 1×
“Ku-0063794 and Ku-0068650 47,48 , developed by KuDOS Pharmaceuticals (now part of AstraZeneca), are also examples of early ATP-competitive mTOR inhibitors which exhibit great anti-proliferative potential against cancer cells in vitro .”
Background
Vertical Targeting of the Phosphatidylinositol-3 Kinase Pathway as a Strategy for Treating Melanoma
Aziz, S. A., Jilaveanu, L. B., Zito, C. R., Camp, R. L., Rimm, D. L., Conrad, P. J., & Kluger, H. M. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-1490 · Cited by 80 · cited 1×
“Not only does the dual mTOR/PI3K inhibitor NVP-BEZ235 exert potent anti-tumor activity in vivo but its effect can be further enhanced by the combination with inhibitors against other mitogenic pathways, such as the MEK/ERK inhibitors 36,37 .”
Background
Point mutations of the mTOR-RHEB pathway in renal cell carcinoma
Ghosh, A. P., Marshall, C. B., Coric, T., Shim, E., Kirkman, R. L., Ballestas, M. E., Ikura, M., Bjornsti, M., & Sudarshan, S. (2015) · Oncotarget · doi:10.18632/oncotarget.4963 · Cited by 78 · cited 2×
“A final issue compromising the efficacy of mTOR inhibitors is that a wide range 72–76 of clinically relevant mutations in mTOR can increase the catalytic activity of mTOR and thus both mTORC1 and mTORC2, thereby reducing the effectiveness of such compounds toward the first two generations of mTOR…”
Background
Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2)
Barlow, A. D., Xie, J., Moore, C. E., Campbell, S. C., Shaw, J., Nicholson, M. L., & Herbert, T. P. (2012) · Diabetologia · doi:10.1007/s00125-012-2475-7 · Cited by 78 · cited 2×
“…islet transplantations 52 , yet a follow-up study 5 years later has demonstrated that only approximately 10% of the recipients remained insulin independent 53 , likely owing to the fact that mTOR inhibitors would induce pancreatic β -cell death 54,55 as a result of the inhibition of mTORC2 56 .”
Background
Signaling crosstalk between the mTOR complexes
Xie, J., & Proud, C. G. (2014) · Translation · doi:10.4161/trla.28174 · Cited by 60
The SIN1-PH Domain Connects mTORC2 to PI3K
Yuan, H., & Guan, K. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-1125 · Cited by 57 · cited 1×
“It may be linked to the PI3K pathway 17 , which is frequently dysregulated in cancer, for example, by loss of the tumor suppressor protein PTEN (phosphatase and tensin homolog).”
Background
Functional interaction of mammalian target of rapamycin complexes in regulating mammalian cell size and cell cycle
Rosner, M., Fuchs, C., Siegel, N., Valli, A., & Hengstschläger, M. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp271 · Cited by 55
Rapamycin induces transactivation of the EGFR and increases cell survival
Chaturvedi, D., Gao, X., Cohen, M. S., Taunton, J., & Patel, T. B. (2009) · Oncogene · doi:10.1038/onc.2008.490 · Cited by 52 · cited 1×
“…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. various feedback loops which, for example, promote activation of the oncogenic PI3K/Akt pathway 24,25 .”
Background
Differing effects of rapamycin and mTOR kinase inhibitors on protein synthesis
Huo, Y., Iadevaia, V., & Proud, C. G. (2011) · Biochemical Society Transactions · doi:10.1042/bst0390446 · Cited by 47
Structural insights of mTOR complex 1
Yuan, H., & Guan, K. (2016) · Cell Research · doi:10.1038/cr.2016.10 · Cited by 38 · cited 1×
“DI NVP-BEZ235 (dactolisib) Phase I/II (22) Novartis MBC/pNET 35”
Targeting Eukaryotic Translation in Mesothelioma Cells with an eIF4E-Specific Antisense Oligonucleotide
Jacobson, B. A., Thumma, S. C., Jay-Dixon, J., Patel, M. R., Kroening, K. D., Kratzke, M. G., Etchison, R. G., Konicek, B. W., Graff, J. R., & Kratzke, R. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081669 · Cited by 37 · cited 1×
“Alternative ways of impairing eIF4E function may be effective in such settings; possibilities include the use of anti-sense RNAs against its mRNA 61 , and blocking its binding to its partner eIF4G 62 .”
Background

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See all 268

Authors: Xie, J., Wang, X., & Proud, C. G.
Affiliations: South Australian Health and Medical Research Institute (AU)
Corresponding author: Proud, Christopher G.
ORCID: Xie, Jianling
Wang, Xuemin
Proud, Christopher G.
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: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (unspecified)
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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