537
Views
15
CrossRef citations to date
0
Altmetric
Review Article

Recent advances in targeting mTOR signaling pathway using small molecule inhibitors

&
Pages 189-201 | Received 02 Jun 2016, Accepted 05 Sep 2016, Published online: 03 Oct 2016

References

  • Smerdon SJ. A year in structural signaling: mTOR-the PIKK of the bunch? Sci Signal 2014;7:pe6.
  • Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5:671–88.
  • Populo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012;13:1886–918.
  • Vander Haar E, Lee SI, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316–23.
  • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606–19.
  • Daneshmanesh AH, Hojjat-Farsangi M, Moshfegh A, et al. The PI3K/AKT/mTOR pathway is involved in direct apoptosis of CLL cells induced by ROR1 monoclonal antibodies. Br J Haematol 2015;169:455–8.
  • Sato T, Nakashima A, Guo L, et al. Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 2010;29:2746–52.
  • Khamisipour G, Jadidi-Niaragh F, Jahromi AS, et al. Mechanisms of tumor cell resistance to the current targeted-therapy agents. Tumor Biol 2016;37:10021–39.
  • Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci 2014;15:13768–801.
  • Hojjat-Farsangi M. Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances. J Drug Target 2016;24:192–211.
  • Lv X, Ma X, Hu Y. Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. Expert Opin Drug Discov 2013;8:991–1012.
  • Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274–93.
  • Wang Z, Zhong J, Inuzuka H, et al. An evolving role for DEPTOR in tumor development and progression. Neoplasia 2012;14:368–75.
  • Wang X, Proud CG. mTORC2 is a tyrosine kinase. Cell Res 2016;26:266.
  • Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137:873–86.
  • Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 2003;11:895–904.
  • Kakumoto K, Ikeda J-i, Okada M, et al. mLST8 promotes mTOR-mediated tumor progression. PLoS One 2015;10:e0119015.
  • Kaizuka T, Hara T, Oshiro N, et al. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J Biol Chem 2010;285:20109–16.
  • Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007;25:903–15.
  • Wiza C, Nascimento EB, Ouwens DM. Role of PRAS40 in Akt and mTOR signaling in health and disease. Am J Physiol. Endocrinol Metab 2012;302:E1453–60.
  • Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002;110:177–89.
  • Bian Y, Wang Z, Xu J, et al. Elevated Rictor expression is associated with tumor progression and poor prognosis in patients with gastric cancer. Biochem Biophys Res Commun 2015;464:534–40.
  • Sarbassov DD, Ali SM, Kim D-H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004;14:1296–302.
  • Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 2006;16:1865–70.
  • Liu P, Gan W, Inuzuka H, et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis. Nat Cell Biol 2013;15:1340–50.
  • Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J 2007;405:513–22.
  • Dibble CC, Elis W, Menon S, et al. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell 2012;47:535–46.
  • Huang J, Manning BD. The TSC1–TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008;412:179–90.
  • Ohsawa M, Kobayashi T, Okura H, et al. TSC1 controls distribution of actin fibers through its effect on function of Rho family of small GTPases and regulates cell migration and polarity. PLoS One 2013;8:e54503.
  • Inoki K, Li Y, Zhu T, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648–57.
  • Armijo ME, Campos T, Fuentes‐Villalobos F, et al. Rheb signaling and tumorigenesis: mTORC1 and new horizons. Int J Cancer 2016;138:1815–23.
  • Tyagi R, Shahani N, Gorgen L, et al. Rheb inhibits protein synthesis by activating the PERK-eIF2α signaling cascade. Cell Rep 2015;10:684–93.
  • Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr Biol 1997;7:261–9.
  • Garami A, Zwartkruis FJ, Nobukuni T, et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol Cell 2003;11:1457–66.
  • Dibble CC, Cantley LC. Regulation of mTORC1 by PI3K signaling. Trends Cell Biol 2015;25:545–55.
  • Worby CA, Dixon JE. PTEN. Annu Rev Biochem 2014;83:641–69.
  • Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 2007;8:774–85.
  • Inoki K, Zhu T, Guan K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577–90.
  • Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214–26.
  • Sancak Y, Peterson TR, Shaul YD, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496–501.
  • Shaw RJ, Bardeesy N, Manning BD, et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004;6:91–9.
  • Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer 2009;9:563–75.
  • Zhou W, Zhang J, Marcus AI. LKB1 tumor suppressor: therapeutic opportunities knock when LKB1 is inactivated. Genes Dis 2014;1:64–74.
  • Reiling JH, Hafen E. The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 2004;18:2879–92.
  • Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem 2003;278:29655–60.
  • Solaini G, Baracca A, Lenaz G, et al. Hypoxia and mitochondrial oxidative metabolism. Biochimica Et Biophysica Acta (BBA)-Bioenergetics 2010;1797:1171–7.
  • Faubert B, Vincent EE, Poffenberger MC, et al. The AMP-activated protein kinase (AMPK) and cancer: Many faces of a metabolic regulator. Cancer Lett 2015;356:165–70.
  • Kaur S, Sassano A, Dolniak B, et al. Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc Natl Acad Sci USA 2008;105:4808–13.
  • Ozes ON, Mayo LD, Gustin JA, et al. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 1999;401:82–5.
  • Qiu L, Zhang L, Zhu L, et al. PI3K/Akt mediates expression of TNF-alpha mRNA and activation of NF-kappaB in calyculin A-treated primary osteoblasts. Oral Diseases 2008;14:727–33.
  • Kroczynska B, Kaur S, Platanias LC. Growth suppressive cytokines and the AKT/mTOR pathway. Cytokine 2009;48:138–43.
  • Powell JD, Pollizzi KN, Heikamp EB, et al. Regulation of immune responses by mTOR. Annu Rev Immunol 2012;30:39
  • Sekiguchi T, Hirose E, Nakashima N, et al. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem 2001;276:7246–57.
  • Wolfson RL, Chantranupong L, Saxton RA, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 2016;351:43–8.
  • Chantranupong L, Scaria SM, Saxton RA, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell 2016;165:153–64.
  • Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013;340:1100–6.
  • Gingras A-C, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001;15:807–26.
  • Martin KA, Blenis J. Coordinate regulation of translation by the PI 3-kinase and mTOR pathways. Adv Cancer Res 2002;86:1–39.
  • Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009;10:307–18.
  • Hojjat-Farsangi M. Novel and emerging targeted-based cancer therapy agents and methods. Tumour Biol 2015;36:543–56.
  • Mizushima N, Klionsky DJ. Protein turnover via autophagy: implications for metabolism. Annu Rev Nutr 2007;27:19–40.
  • Dunlop EA, Hunt DK, Acosta-Jaquez HA, et al. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 2011;7:737–47.
  • Jung CH, Seo M, Otto NM, et al. ULK1 inhibits the kinase activity of mTORC1 and cell proliferation. Autophagy 2011;7:1212–21.
  • Yu Y, Yoon S-O, Poulogiannis G, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011;332:1322–6.
  • Liu B, Liu F. Feedback regulation of mTORC1 by Grb10 in metabolism and beyond. Cell Cycle 2014;13:2643–4.
  • Peterson TR, Sengupta SS, Harris TE, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011;146:408–20.
  • Bakan I, Laplante M. Connecting mTORC1 signaling to SREBP-1 activation. Curr Opin Lipidol 2012;23:226–34.
  • Zinzalla V, Stracka D, Oppliger W, et al. Activation of mTORC2 by association with the ribosome. Cell 2011;144:757–68.
  • Tato I, Bartrons R, Ventura F, et al. Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J Biol Chem 2011;286:6128–42.
  • Liu H, Liu R, Xiong Y, et al. Leucine facilitates the insulin-stimulated glucose uptake and insulin signaling in skeletal muscle cells: involving mTORC1 and mTORC2. Amino Acids 2014;46:1971–9.
  • Gaubitz C, Prouteau M, Kusmider B, et al. TORC2 Structure and Function. Trends Biochem Sci 2016;41:532–45.
  • Zhou H, Huang S. Role of mTOR signaling in tumor cell motility, invasion and metastasis. Curr Protein Pept Sci 2011;12:30.
  • García-Martínez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum-and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375–85.
  • Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098–101.
  • Ikenoue T, Inoki K, Yang Q, et al. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signaling. EMBO J 2008;27:1919–31.
  • Yang G, Murashige DS, Humphrey SJ, et al. A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep 2015;12:937–43.
  • Zask A, Verheijen JC, Richard DJ. Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review. Expert Opin Ther Pat 2011;21:1109–27.
  • Wahdan-Alaswad RS, Bane KL, Song K, et al. Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. Mol Cancer Res 2012;10:821–33.
  • Soares HP, Ni Y, Kisfalvi K, et al. Different patterns of Akt and ERK feedback activation in response to rapamycin, active-site mTOR inhibitors and metformin in pancreatic cancer cells. PLoS One 2013;8:e57289.
  • Lee SL, Chou CC, Chuang HC, et al. Functional role of mTORC2 versus integrin-linked kinase in mediating Ser473-Akt phosphorylation in PTEN-negative prostate and breast cancer cell lines. PLoS One 2013;8:e67149.
  • Li H, Zeng J, Shen K. PI3K/AKT/mTOR signaling pathway as a therapeutic target for ovarian cancer. Arch Gynecol Obstet 2014;290:1067–78.
  • Fei SJ, Zhang XC, Dong S, et al. Targeting mTOR to overcome epidermal growth factor receptor tyrosine kinase inhibitor resistance in non-small cell lung cancer cells. PLoS One 2013;8:e69104.
  • Yongxi T, Haijun H, Jiaping Z, et al. Autophagy inhibition sensitizes KU-0063794-mediated anti-HepG2 hepatocellular carcinoma cell activity in vitro and in vivo. Biochem Biophys Res Commun 2015;465:494–500.
  • Ghosh AP, Marshall CB, Coric T, et al. Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget 2015;6:17895–910.
  • Schwarzer A, Holtmann H, Brugman M, et al. Hyperactivation of mTORC1 and mTORC2 by multiple oncogenic events causes addiction to eIF4E-dependent mRNA translation in T-cell leukemia. Oncogene 2015;34:3593–604.
  • Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second generation of inhibitors. Mol Cancer Ther 2011;10:395–403.
  • Huang S, Bjornsti MA, Houghton PJ. Rapamycins: mechanism of action and cellular resistance. Cancer Biol Ther 2003;2:222–32.
  • Oshiro N, Yoshino K, Hidayat S, et al. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 2004;9:359–66.
  • Schenone S, Brullo C, Musumeci F, et al. ATP-competitive inhibitors of mTOR: an update. Curr Med Chem 2011;18:2995–3014.
  • Shor B, Zhang WG, Toral-Barza L, et al. A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 2008;68:2934–43.
  • Meng LH, Zheng XF. Toward rapamycin analog (rapalog)-based precision cancer therapy. Acta Pharmacol Sin 2015;36:1163–9.
  • Peterson DE, O'Shaughnessy JA, Rugo HS, et al. Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice. Cancer Med 2016;5:1897–907.
  • Shameem R, Lacouture M, Wu S. Incidence and risk of rash to mTOR inhibitors in cancer patients-a meta-analysis of randomized controlled trials. Acta Oncol 2015;54:124–32.
  • Rivera VM, Squillace RM, Miller D, et al. Ridaforolimus (AP23573; MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 2011;10:1059–71.
  • Legrier ME, Yang CP, Yan HG, et al. Targeting protein translation in human non small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. Cancer Res 2007;67:11300–8.
  • Piha-Paul SA, Munster PN, Hollebecque A, et al. Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours. Eur J Cancer 2015;51:1865–73.
  • Hartford CM, Desai AA, Janisch L, et al. A phase I trial to determine the safety, tolerability, and maximum tolerated dose of deforolimus in patients with advanced malignancies. Clin Cancer Res 2009;15:1428–34.
  • Saran U, Foti M, Dufour JF. Cellular and molecular effects of the mTOR inhibitor everolimus. Clin Sci (Lond) 2015;129:895–914.
  • Baroja-Mazo A, Revilla-Nuin B, Ramirez P, et al. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J Transplant 2016;6:183–92.
  • Doi T, Muro K, Boku N, et al. Multicenter phase II study of everolimus in patients with previously treated metastatic gastric cancer. J Clin Oncol 2010;28:1904–10.
  • Lombard-Bohas C, Yao JC, Hobday T, et al. Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas 2015;44:181–9.
  • Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016;387:968–77.
  • Pantano F, Santoni M, Procopio G, et al. The changes of lipid metabolism in advanced renal cell carcinoma patients treated with everolimus: a new pharmacodynamic marker? PLoS One 2015;10:e0120427.
  • Mita MM, Mita A, Rowinsky EK. The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2003;2:S169–77.
  • Vignot S, Faivre S, Aguirre D, et al. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 2005;16:525–37.
  • Baldo P, Cecco S, Giacomin E, et al. mTOR pathway and mTOR inhibitors as agents for cancer therapy. Curr Cancer Drug Targets 2008;8:647–65.
  • Fasolo A, Sessa C. Targeting mTOR pathways in human malignancies. Curr Pharm Des 2012;18:2766–77.
  • Zhang YJ, Duan Y, Zheng XF. Targeting the mTOR kinase domain: the second generation of mTOR inhibitors. Drug Discov Today 2011;16:325–31.
  • Takeuchi CS, Kim BG, Blazey CM, et al. Discovery of a novel class of highly potent, selective, ATP-competitive, and orally bioavailable inhibitors of the mammalian target of rapamycin (mTOR). J Med Chem 2013;56:2218–34.
  • Garcia-Martinez JM, Moran J, Clarke RG, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 2009;421:29–42.
  • Feldman ME, Apsel B, Uotila A, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 2009;7:e38.
  • Koo J, Yue P, Deng X, et al. mTOR complex 2 stabilizes Mcl-1 protein by suppressing its glycogen synthase kinase 3-dependent and SCF-FBXW7-mediated degradation. Mol Cell Biol 2015;35:2344–55.
  • Gordeev SA, Bykova TV, Zubova SG, et al. mTOR kinase inhibitor pp242 causes mitophagy terminated by apoptotic cell death in E1A-Ras transformed cells. Oncotarget 2015;6:44905–26.
  • Thoreen CC, Kang SA, Chang JW, et al. An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 2009;284:8023–32.
  • Karlsson E, Pérez-Tenorio G, Amin R, et al. The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomized Stockholm tamoxifen trials. Breast Cancer Res 2013;15:1–14.
  • Avniel-Polak S, Leibowitz G, Riahi Y, et al. Abrogation of autophagy by chloroquine alone or in combination with mTOR inhibitors induces apoptosis in neuroendocrine tumor cells. Neuroendocrinology 2015;103. [Epub ahead of print]. doi: 10.1159/000442589.
  • Rubinfeld H, Cohen O, Kammer A, et al. Combination of mTOR inhibitors augments potency while activating PI3K signaling in pituitary tumors. Neuroendocrinology 2016;103:592–604.
  • Garcia-Garcia C, Ibrahim YH, Serra V, et al. Dual mTORC1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res 2012;18:2603–12.
  • Lou HZ, Weng XC, Pan HM, et al. The novel mTORC1/2 dual inhibitor INK-128 suppresses survival and proliferation of primary and transformed human pancreatic cancer cells. Biochem Biophys Res Commun 2014;450:973–8.
  • Li C, Cui JF, Chen MB, et al. The preclinical evaluation of the dual mTORC1/2 inhibitor INK-128 as a potential anti-colorectal cancer agent. Cancer Biol Ther 2015;16:34–42.
  • Jiang SJ, Wang S. Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo. Tumour Biol 2015;36:8177–84.
  • Altman MK, Alshamrani AA, Jia W, et al. Suppression of the GTPase-activating protein RGS10 increases Rheb-GTP and mTOR signaling in ovarian cancer cells. Cancer Lett 2015;369:175–83.
  • Jiang H, Zeng Z. Dual mTORC1/2 inhibition by INK-128 results in antitumor activity in preclinical models of osteosarcoma. Biochem Biophys Res Commun 2015;468:255–61.
  • Yu K, Shi C, Toral-Barza L, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 2010;70:621–31.
  • Zhang D, Xia H, Zhang W, et al. The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor. Tumour Biol 2016;37:1327–36.
  • Rastogi R, Jiang Z, Ahmad N, et al. Rapamycin induces mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) expression through activation of protein kinase B and mitogen-activated protein kinase kinase pathways. J Biol Chem 2013;288:33966–77.
  • Kahn J, Hayman TJ, Jamal M, et al. The mTORC1/mTORC2 inhibitor AZD2014 enhances the radiosensitivity of glioblastoma stem-like cells. Neuro-oncology 2014;16:29–37.
  • Guichard SM, Curwen J, Bihani T, et al. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER + breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther 2015;14:2508–18.
  • Zheng B, Mao JH, Qian L, et al. Pre-clinical evaluation of AZD-2014, a novel mTORC1/2 dual inhibitor, against renal cell carcinoma. Cancer Lett 2015;357:468–75.
  • Liao H, Huang Y, Guo B, et al. Dramatic antitumor effects of the dual mTORC1 and mTORC2 inhibitor AZD2014 in hepatocellular carcinoma. Am J Cancer Res 2015;5:125–39.
  • Basu B, Dean E, Puglisi M, et al. First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014. Clin Cancer Res 2015;21:3412–19.
  • Beauchamp RL, James MF, DeSouza PA, et al. A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget 2015;6:16981–97.
  • Hall BA, Kim TY, Skor MN, et al. Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: requirement for mTORC1 activity associates with ER-alpha expression. Breast Cancer Res Treat 2012;135:469–79.
  • Singleton KR, Hinz TK, Kleczko EK, et al. Kinome RNAi screens reveal synergistic targeting of MTOR and FGFR1 pathways for treatment of lung cancer and HNSCC. Cancer Res 2015;75:4398–406.
  • Powles T, Wheater M, Din O, et al. A randomised phase 2 study of AZD2014 versus everolimus in patients with VEGF-refractory metastatic clear cell renal cancer. Eur Urol 2016;69:450–6.
  • Ezell SA, Mayo M, Bihani T, et al. Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma. Oncotarget 2014;5:4990–5001.
  • Harada M, Benito J, Yamamoto S, et al. The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression. Oncotarget 2015;6:37930–47.
  • Kokhaei P, Jadidi-Niaragh F, Sotoodeh Jahromi A, et al. Ibrutinib-A double-edge sword in cancer and autoimmune disorders. J Drug Target 2016;24:373–85.
  • Brachmann S, Fritsch C, Maira SM, et al. PI3K and mTOR inhibitors: a new generation of targeted anticancer agents. Curr Opin Cell Biol 2009;21:194–8.
  • Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627–44.
  • Maira SM, Voliva C, Garcia-Echeverria C. Class IA phosphatidylinositol 3-kinase: from their biologic implication in human cancers to drug discovery. Expert Opin Ther Targets 2008;12:223–38.
  • Rafii S, Roda D, Geuna E, et al. Higher risk of infections with PI3K-AKT-mTOR pathway inhibitors in patients with advanced solid tumors on phase I clinical trials. Clin Cancer Res 2015;21:1869–76.
  • Geuna E, Roda D, Rafii S, et al. Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials. Br J Cancer 2015;113:1541–7.
  • Yu K, Toral-Barza L, Shi C, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009;69:6232–40.
  • Jhanwar-Uniyal M, Gillick JL, Neil J, et al. Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: a tale of two complexes. Adv Biol Regul 2015;57:64–74.
  • Weber H, Leal P, Stein S, et al. Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice. Oncotarget 2015;6:31877–88.
  • Wu L, Zhang J, Wu H, et al. DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600. Biochem Biophys Res Commun 2015;466:547–53.
  • Cheng F, Wang L, Shen Y, et al. Preclinical evaluation of WYE-687, a mTOR kinase inhibitor, as a potential anti-acute myeloid leukemia agent. Biochem Biophys Res Commun 2016;470:324–30.
  • Ravikumar B, Stewart A, Kita H, et al. Raised intracellular glucose concentrations reduce aggregation and cell death caused by mutant huntingtin exon 1 by decreasing mTOR phosphorylation and inducing autophagy. Hum Mol Genet 2003;12:985–94.
  • Naing A, Aghajanian C, Raymond E, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012;107:1093–9.
  • Maira SM, Stauffer F, Brueggen J, et al. 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. Mol Cancer Ther 2008;7:1851–63.
  • Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341–9.
  • Papadopoulos KP, Egile C, Ruiz-Soto R, et al. Efficacy, safety, pharmacokinetics and pharmacodynamics of SAR245409 (voxtalisib, XL765), an orally administered phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor: a phase 1 expansion cohort in patients with relapsed or refractory lymphoma. Leuk Lymphoma 2015;56:1763–70.
  • Bhagwat SV, Gokhale PC, Crew AP, et al. Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Mol Cancer Ther 2011;10:1394–406.
  • Xue Q, Hopkins B, Perruzzi C, et al. Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability. Cancer Res 2008;68:9551–7.
  • Venkatesan AM, Dehnhardt CM, Delos Santos E, et al. Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J Med Chem 2010;53:2636–45.
  • Rodrik-Outmezguine VS, Okaniwa M, Yao Z, et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 2016;534:272–6.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.