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Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy

Oncogene volume 29, pages 3733–3744 (2010)Cite this article

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Abstract

Small molecule inhibitors that selectively target cancer cells and not normal cells would be valuable anti-cancer therapeutics. The mammalian target of rapamycin complex 2 (mTORC2) is emerging as a promising candidate target for such an inhibitor. Recent studies in cancer biology indicate that mTORC2 activity is essential for the transformation and vitality of a number of cancer cell types, but in many normal cells, mTORC2 activity is less essential. These studies are intensifying interest in developing inhibitors that specifically target mTORC2. However, there are many open questions regarding the function and regulation of mTORC2 and its function in both normal and cancer cells. Here, we summarize exciting new research into the biology of mTORC2 signaling and highlight the current state and future prospects for mTOR-targeted therapy.

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References

  • Acosta-Jaquez HA, Keller JA, Foster KG, Ekim B, Soliman GA, Feener EP et al. (2009). Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. Mol Cell Biol 29: 4308–4324.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Akcakanat A, Singh G, Hung MC, Meric-Bernstam F . (2007). Rapamycin regulates the phosphorylation of rictor. Biochem Biophys Res Commun 362: 330–333.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P et al. (1996). Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15: 6541–6551.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Aronova S, Wedaman K, Aronov PA, Fontes K, Ramos K, Hammock BD et al. (2008). Regulation of ceramide biosynthesis by TOR complex 2. Cell Metab 7: 148–158.

    CAS  PubMed  Google Scholar 

  • Audhya A, Loewith R, Parsons AB, Gao L, Tabuchi M, Zhou H et al. (2004). Genome-wide lethality screen identifies new PI4,5P2 effectors that regulate the actin cytoskeleton. EMBO J 23: 3747–3757.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Barquilla A, Crespo JL, Navarro M . (2008). Rapamycin inhibits trypanosome cell growth by preventing TOR complex 2 formation. Proc Natl Acad Sci USA 105: 14579–14584.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bentzinger CF, Romanino K, Cloetta D, Lin S, Mascarenhas JB, Oliveri F et al. (2008). Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab 8: 411–424.

    CAS  PubMed  Google Scholar 

  • Berchtold D, Walther TC . (2009). TORC2 plasma membrane localization is essential for cell viability and restricted to a distinct domain. Mol Biol Cell 20: 1565–1575.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bozulic L, Hemmings BA . (2009). PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol 21: 256–261.

    CAS  PubMed  Google Scholar 

  • Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A et al. (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118: 3065–3074.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE et al. (2010). AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 70: 288–298.

    CAS  PubMed  Google Scholar 

  • Copp J, Manning G, Hunter T . (2009). TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2. Cancer Res 69: 1821–1827.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cybulski N, Polak P, Auwerx J, Ruegg MA, Hall MN . (2009). mTOR complex 2 in adipose tissue negatively controls whole-body growth. Proc Natl Acad Sci USA 106: 9902–9907.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dibble CC, Asara JM, Manning BD . (2009). Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol 29: 5657–5670.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Efeyan A, Sabatini DM . (2009). mTOR and cancer: many loops in one pathway. Curr Opin Cell Biol 22: 1–8.

    Google Scholar 

  • Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R et al. (2008). Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14: 1351–1356.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C et al. (2008). The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27: 1932–1943.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fadri M, Daquinag A, Wang S, Xue T, Kunz J . (2005). The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2. Mol Biol Cell 16: 1883–1900.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al. (2009). Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7: e38.

    PubMed  Google Scholar 

  • Frias MA, Thoreen CC, Jaffe JD, Schroder W, Sculley T, Carr SA et al. (2006). mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol 16: 1865–1870.

    CAS  PubMed  Google Scholar 

  • Gangloff YG, Mueller M, Dann SG, Svoboda P, Sticker M, Spetz JF et al. (2004). Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24: 9508–9516.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garcia-Martinez JM, Alessi DR . (2008). mTOR complex-2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum and glucocorticoid induced protein kinase-1 (SGK1). Biochem J 416: 375–385.

    CAS  PubMed  Google Scholar 

  • Garcia-Martinez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM et al. (2009). Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 421: 29–42.

    CAS  PubMed  Google Scholar 

  • Guertin DA, Sabatini DM . (2007). Defining the role of mTOR in cancer. Cancer Cell 12: 9–22.

    CAS  PubMed  Google Scholar 

  • Guertin DA, Sabatini DM . (2009). The pharmacology of mTOR inhibition. Sci Signal 2: pe24.

    PubMed  Google Scholar 

  • Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH et al. (2009). mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell 15: 148–159.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J et al. (2006). 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 11: 859–871.

    CAS  PubMed  Google Scholar 

  • Gulhati P, Cai Q, Li J, Liu J, Rychahou PG, Qiu S et al. (2009). Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer. Clin Cancer Res 15: 7207–7216.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S et al. (2002). Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110: 177–189.

    Article  CAS  PubMed  Google Scholar 

  • Hayashi T, Hatanaka M, Nagao K, Nakaseko Y, Kanoh J, Kokubu A et al. (2007). Rapamycin sensitivity of the Schizosaccharomyces pombe tor2 mutant and organization of two highly phosphorylated TOR complexes by specific and common subunits. Genes Cells 12: 1357–1370.

    CAS  PubMed  Google Scholar 

  • Hietakangas V, Cohen SM . (2007). Re-evaluating AKT regulation: role of TOR complex 2 in tissue growth. Genes Dev 21: 632–637.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hietakangas V, Cohen SM . (2008). TOR complex 2 is needed for cell cycle progression and anchorage-independent growth of MCF7 and PC3 tumor cells. BMC Cancer 8: 282.

    PubMed  PubMed Central  Google Scholar 

  • Hresko RC, Mueckler M . (2005). mTOR/RICTOR is the Ser473 kinase for Akt/PKB in 3T3-L1 adipocytes. J Biol Chem 280: 40406–40416.

    CAS  PubMed  Google Scholar 

  • Huang J, Dibble CC, Matsuzaki M, Manning BD . (2008). The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 28: 4104–4115.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Manning BD . (2008). The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 412: 179–190.

    CAS  PubMed  Google Scholar 

  • Huang J, Wu S, Wu CL, Manning BD . (2009). Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. Cancer Res 69: 6107–6114.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ikenoue T, Inoki K, Yang Q, Zhou X, Guan KL . (2008). Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. EMBO J 27: 1919–1931.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY et al. (2006). SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127: 125–137.

    CAS  PubMed  Google Scholar 

  • Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A et al. (2004). Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6: 1122–1128.

    CAS  PubMed  Google Scholar 

  • Jacinto E, Lorberg A . (2008). TOR regulation of AGC kinases in yeast and mammals. Biochem J 410: 19–37.

    CAS  PubMed  Google Scholar 

  • Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA et al. (2010). Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 16: 205–213.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jones KT, Greer ER, Pearce D, Ashrafi K . (2009). Rictor/TORC2 regulates Caenorhabditis elegans fat storage, body size, and development through sgk-1. PLoS Biol 7: e60.

    PubMed  Google Scholar 

  • Julien LA, Carriere A, Moreau J, Roux PP . (2009). mTORC1-activated S6K1 phosphorylates Rictor on Threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 30: 908–921.

    PubMed  PubMed Central  Google Scholar 

  • Kamada Y, Fujioka Y, Suzuki NN, Inagaki F, Wullschleger S, Loewith R et al. (2005). Tor2 directly phosphorylates the AGC kinase Ypk2 to regulate actin polarization. Mol Cell Biol 25: 7239–7248.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kamimura Y, Xiong Y, Iglesias PA, Hoeller O, Bolourani P, Devreotes PN . (2008). PIP3-independent activation of TorC2 and PKB at the cell′s leading edge mediates chemotaxis. Curr Biol 18: 1034–1043.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim D-H, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H et al. (2002). mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110: 163–175.

    CAS  PubMed  Google Scholar 

  • Kim DH, Sarbassov dos D, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H et al. (2003). GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell 11: 895–904.

    CAS  PubMed  Google Scholar 

  • Kim E, Guan KL . (2009). RAG GTPases in nutrient-mediated TOR signaling pathway. Cell Cycle 8: 1014–1018.

    CAS  PubMed  Google Scholar 

  • Koike-Kumagai M, Yasunaga K, Morikawa R, Kanamori T, Emoto K . (2009). The target of rapamycin complex 2 controls dendritic tiling of Drosophila sensory neurons through the Tricornered kinase signalling pathway. EMBO J 28: 3879–3892.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Harris TE, Keller SR, Choi KM, Magnuson MA, Lawrence Jr JC . (2008). Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances Basal glycogen synthase activity. Mol Cell Biol 28: 61–70.

    CAS  PubMed  Google Scholar 

  • Laplante M, Sabatini DM . (2009a). An emerging role of mTOR in lipid biosynthesis. Curr Biol 19: R1046–R1052.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Laplante M, Sabatini DM . (2009b). mTOR signaling at a glance. J Cell Sci 122: 3589–3594.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Comer FI, Sasaki A, McLeod IX, Duong Y, Okumura K et al. (2005). TOR complex 2 integrates cell movement during chemotaxis and signal relay in dictyostelium. Mol Biol Cell 16: 4572–4583.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Parent CA, Insall R, Firtel RA . (1999). A novel Ras-interacting protein required for chemotaxis and cyclic adenosine monophosphate signal relay in dictyostelium. Mol Biol Cell 10: 2829–2845.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu P, Cheng H, Roberts TM, Zhao JJ . (2009). Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8: 627–644.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Loewith R, Jacinto E, Wullschleger S, Lorberg A, Crespo JL, Bonenfant D et al. (2002). Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10: 457–468.

    CAS  PubMed  Google Scholar 

  • Manning BD, Cantley LC . (2007). AKT/PKB signaling: navigating downstream. Cell 129: 1261–1274.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martiny-Baron G, Fabbro D . (2007). Classical PKC isoforms in cancer. Pharmacol Res 55: 477–486.

    CAS  PubMed  Google Scholar 

  • Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A et al. (2007). mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res 67: 11712–11720.

    CAS  PubMed  Google Scholar 

  • McManus EJ, Collins BJ, Ashby PR, Prescott AR, Murray-Tait V, Armit LJ et al. (2004). The in vivo role of PtdIns(3,4,5)P3 binding to PDK1 PH domain defined by knockin mutation. EMBO J 23: 2071–2082.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F et al. (2004). mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 24: 6710–6718.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nardella C, Carracedo A, Alimonti A, Hobbs RM, Clohessy JG, Chen Z et al. (2009). Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Sci Signal 2: ra2.

    PubMed  PubMed Central  Google Scholar 

  • Nojima H, Tokunaga C, Eguchi S, Oshiro N, Hidayat S, Yoshino K et al. (2003). The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem 278: 15461–15464.

    CAS  PubMed  Google Scholar 

  • O′Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508.

    PubMed  PubMed Central  Google Scholar 

  • Pearce LR, Huang X, Boudeau J, Pawlowski R, Wullschleger S, Deak M et al. (2007). Identification of Protor as a novel Rictor-binding component of mTOR-complex-2. Biochem J 405: 513–522.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peterson TR, Laplante M, Thoreen CC, Sancak Y, Kang SA, Kuehl WM et al. (2009). DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137: 873–886.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveros M, Perruzzi C et al. (2006). Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10: 159–170.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Recher C, Dos Santos C, Demur C, Payrastre B . (2005). mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle 4: 1540–1549.

    CAS  PubMed  Google Scholar 

  • Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L et al. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320: 1496–1501.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sarbassov D, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF et al. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22: 159–168.

    CAS  PubMed  Google Scholar 

  • Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al. (2004). Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14: 1296–1302.

    CAS  PubMed  Google Scholar 

  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . (2005). Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307: 1098–1101.

    CAS  PubMed  Google Scholar 

  • Schalm SS, Blenis J . (2002). Identification of a conserved motif required for mTOR signaling. Curr Biol 12: 632–639.

    CAS  PubMed  Google Scholar 

  • Schalm SS, Fingar DC, Sabatini DM, Blenis J . (2003). TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 13: 797–806.

    CAS  PubMed  Google Scholar 

  • Schroder W, Bushell G, Sculley T . (2005). The human stress-activated protein kinase-interacting 1 gene encodes JNK-binding proteins. Cell Signal 17: 761–767.

    CAS  PubMed  Google Scholar 

  • Schroder WA, Buck M, Cloonan N, Hancock JF, Suhrbier A, Sculley T et al. (2007). Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signallling. Cell Signal 19: 1279–1289.

    CAS  PubMed  Google Scholar 

  • Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA . (2006). Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 11: 583–589.

    CAS  PubMed  Google Scholar 

  • Shor B, Gibbons JJ, Abraham RT, Yu K . (2009). Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 8: 3831–3837.

    CAS  PubMed  Google Scholar 

  • Shor B, Zhang WG, Toral-Barza L, Lucas J, Abraham RT, Gibbons JJ et al. (2008). A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Cancer Res 68: 2934–2943.

    CAS  PubMed  Google Scholar 

  • Soukas AA, Kane EA, Carr CE, Melo JA, Ruvkun G . (2009). Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev 23: 496–511.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sturgill TW, Cohen A, Diefenbacher M, Trautwein M, Martin DE, Hall MN . (2008). TOR1 and TOR2 have distinct locations in live cells. Eukaryot Cell 7: 1819–1830.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tabuchi M, Audhya A, Parsons AB, Boone C, Emr SD . (2006). The phosphatidylinositol 4,5-biphosphate and TORC2 binding proteins Slm1 and Slm2 function in sphingolipid regulation. Mol Cell Biol 26: 5861–5875.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tessier M, Woodgett JR . (2006). Serum and glucocorticoid-regulated protein kinases: variations on a theme. J Cell Biochem 98: 1391–1407.

    CAS  PubMed  Google Scholar 

  • Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, Jeno P et al. (2007). PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2: e1217.

    PubMed  PubMed Central  Google Scholar 

  • Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y et al. (2009). An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284: 8023–8032.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Treins C, Warne PH, Magnuson MA, Pende M, Downward J . (2009). Rictor is a novel target of p70 S6 kinase-1. Oncogene 29: 1003–1016.

    PubMed  Google Scholar 

  • Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ et al. (2009). AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16: 21–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Proud CG . (2009). Nutrient control of TORC1, a cell-cycle regulator. Trends Cell Biol 19: 260–267.

    CAS  PubMed  Google Scholar 

  • White E, DiPaola RS . (2009). The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15: 5308–5316.

    PubMed  PubMed Central  Google Scholar 

  • Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P et al. (2005). Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 23: 5347–5356.

    CAS  PubMed  Google Scholar 

  • Witzig TE, Kaufmann SH . (2006). Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol 7: 285–294.

    PubMed  Google Scholar 

  • Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI et al. (2007). PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling. J Biol Chem 282: 25604–25612.

    CAS  PubMed  Google Scholar 

  • Wullschleger S, Loewith R, Hall MN . (2006). TOR signaling in growth and metabolism. Cell 124: 471–484.

    CAS  PubMed  Google Scholar 

  • Wullschleger S, Loewith R, Oppliger W, Hall MN . (2005). Molecular organization of target of rapamycin complex 2. J Biol Chem 280: 30697–30704.

    CAS  PubMed  Google Scholar 

  • Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford D . (2002a). Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol 9: 940–944.

    CAS  PubMed  Google Scholar 

  • Yang J, Cron P, Thompson V, Good VM, Hess D, Hemmings BA et al. (2002b). Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol Cell 9: 1227–1240.

    CAS  PubMed  Google Scholar 

  • Yang Q, Inoki K, Ikenoue T, Guan KL . (2006a). Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev 20: 2820–2832.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Q, Inoki K, Kim E, Guan KL . (2006b). TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci USA 103: 6811–6816.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yu K, Toral-Barza L, Shi C, Zhang WG, Lucas J, Shor B et al. (2009). Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69: 6232–6240.

    CAS  PubMed  Google Scholar 

  • Yuan R, Kay A, Berg WJ, Lebwohl D . (2009). Targeting tumorigenesis: development and use of mTOR inhibitors in cancer therapy. J Hematol Oncol 2: 45.

    PubMed  PubMed Central  Google Scholar 

  • Zeng Z, Sarbassov dos D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C et al. (2007). Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood 109: 3509–3512.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL et al. (2007). PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117: 730–738.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Billington Jr CJ, Pan D, Neufeld TP . (2006). Drosophila target of rapamycin kinase functions as a multimer. Genetics 172: 355–362.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

DAG is supported by grants from the National Institutes of Health (R00 CA129613), the Charles Hood Foundation, and the UMass Center for Clinical and Translational Sciences.

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    C A Sparks & D A Guertin

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Sparks, C., Guertin, D. Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy. Oncogene 29, 3733–3744 (2010). https://doi.org/10.1038/onc.2010.139

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