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mTORC1 and mTORC2 in cancer and the tumor microenvironment

Abstract

The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration and cancer. Although mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. This review will summarize recent advances in dissecting the relative contributions of mTORC1 versus mTORC2 in cancer, their role in tumor-associated blood vessels and tumor immunity, and provide an update on mTOR inhibitors.

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References

  1. Brown EJ, Albers MW, Bum Shin T, ichikawa K, Keith CT, Lane WS et al. A mammalian protein targeted by G1-arresting rapamycin–receptor complex. Nature 1994; 369: 756–758.

    CAS  PubMed  Google Scholar 

  2. Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH . RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994; 78: 35–43.

    CAS  PubMed  Google Scholar 

  3. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  PubMed  Google Scholar 

  4. Sarbassov DD, Ali SM, Kim D-H, Guertin DA, Latek RR, Erdjument-Bromage 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: 1296–1302.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Laplante M, Sabatini DM . mTOR signaling in growth control and disease. Cell 2012; 149: 274–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP . mTOR kinase structure, mechanism and regulation. Nature 2013; 497: 217–223.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Aylett CHS, Sauer E, Imseng S, Boehringer D, Hall MN, Ban N et al. Architecture of human mTOR complex 1. Science 2015; 351: 48–52.

    PubMed  Google Scholar 

  9. Liu P, Gan W, Chin YR, Ogura K, Guo J, Zhang J et al. PtdIns(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 2015; 5: 1194–1209.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Gaubitz C, Oliveira TM, Prouteau M, Leitner A, Karuppasamy M, Konstantinidou G et al. Molecular basis of the rapamycin insensitivity of target of rapamycin complex 2. Mol Cell 2015; 58: 977–988.

    CAS  PubMed  Google Scholar 

  11. Zinzalla V, Stracka D, Oppliger W, Hall MN . Activation of mTORC2 by association with the ribosome. Cell 2011; 144: 757–768.

    CAS  PubMed  Google Scholar 

  12. Thorpe LM, Yuzugullu H, Zhao JJ . PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2014; 15: 7–24.

    Google Scholar 

  13. Inoki K, Li Y, Zhu T, Wu J, Guan K-L . TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol Nature 2002; 4: 648–657.

    CAS  Google Scholar 

  14. Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC . Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol Cell 2002; 10: 151–162.

    CAS  PubMed  Google Scholar 

  15. Potter CJ, Pedraza LG, Xu T . Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol 2002; 4: 658–665.

    CAS  PubMed  Google Scholar 

  16. Inoki K, Li Y, Xu T, Guan K-L . Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17: 1829–1834.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J . Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward rheb. Curr Biol 2003; 13: 1259–1268.

    CAS  PubMed  Google Scholar 

  18. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 2007; 25: 903–915.

    Article  CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  20. Vander Haar E, Lee S-I, Bandhakavi S, Griffin TJ, Kim D-H . Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007; 9: 316–323.

    CAS  PubMed  Google Scholar 

  21. Wang L, Harris TE, Roth RA, Lawrence JC . PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 2007; 282: 20036–20044.

    CAS  PubMed  Google Scholar 

  22. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . Phosphorylation and functional inactivation of TSC2 by Erk: implications for tuberous sclerosisand cancer pathogenesis. Cell 2005; 121: 179–193.

    CAS  PubMed  Google Scholar 

  23. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J . Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA 2004; 101: 13489–13494.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Carrière A, Cargnello M, Julien L-A, Gao H, Bonneil É, Thibault P et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 2008; 18: 1269–1277.

    PubMed  Google Scholar 

  25. Inoki K, Zhu T, Guan K-L . TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577–590.

    CAS  PubMed  Google Scholar 

  26. Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ . Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 1995; 270: 2320–2326.

    CAS  PubMed  Google Scholar 

  27. Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J . Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem 1998; 273: 14484–14494.

    CAS  PubMed  Google Scholar 

  28. Shimobayashi M, Hall MN . Multiple amino acid sensing inputs to mTORC1. Cell Res 2016; 26: 7–20.

    CAS  PubMed  Google Scholar 

  29. Wang S, Tsun Z-Y, Wolfson RL, Shen K, Wyant GA, Plovanich ME et al. Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 2015; 347: 188–194.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 2012; 149: 410–424.

    CAS  PubMed  Google Scholar 

  31. Bonfils G, Jaquenoud M, Bontron S, Ostrowicz C, Ungermann C, De Virgilio C . Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol Cell 2012; 46: 105–110.

    CAS  PubMed  Google Scholar 

  32. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 2015; 351: 43–48.

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Stracka D, Jozefczuk S, Rudroff F, Sauer U, Hall MN . Nitrogen source activates TOR (target of rapamycin) complex 1 via glutamine and independently of Gtr/Rag proteins. J Biol Chem 2014; 289: 25010–25020.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Jewell JL, Kim YC, Russell RC, Yu F-X, Park HW, Plouffe SW et al. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 2015; 347: 194–198.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Fingar DC, Salama S, Tsou C, Harlow E, Blenis J . Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev 2002; 16: 1472–1487.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Dowling RJO, Topisirovic I, Alain T, Bidinosti M, Fonseca BD, Petroulakis E et al. mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 2010; 328: 1172–1176.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Ma XM, Blenis J . Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 2009; 10: 307–318.

    PubMed  Google Scholar 

  39. Holz MK, Ballif BA, Gygi SP, Blenis J . mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell 2005; 123: 569–580.

    CAS  PubMed  Google Scholar 

  40. Browne GJ, Proud CG . A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin. Mol Cell Biol 2004; 24: 2986–2997.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012; 485: 55–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mayer C, Zhao J, Yuan X, Grummt I . mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability. Genes Dev 2004; 18: 423–434.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ . mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci USA 2010; 107: 11823–11828.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Shor B, Wu J, Shakey Q, Toral-Barza L, Shi C, Follettie M et al. Requirement of the mTOR kinase for the regulation of Maf1 phosphorylation and control of RNA polymerase III-dependent transcription in cancer cells. J Biol Chem 2010; 285: 15380–15392.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H et al. The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 2004; 166: 213–223.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431: 200–205.

    CAS  PubMed  Google Scholar 

  47. Shah OJ, Wang Z, Hunter T . Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr Biol 2004; 14: 1650–1656.

    CAS  PubMed  Google Scholar 

  48. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011; 332: 1317–1322.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Yu Y, Yoon S-O, Poulogiannis G, Yang Q, Ma XM, Villén J et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science 2011; 332: 1322–1326.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004; 10: 594–601.

    CAS  PubMed  Google Scholar 

  51. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010; 39: 171–183.

    PubMed  PubMed Central  Google Scholar 

  52. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011; 146: 408–420.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8: 224–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Ricoult SJH, Yecies JL, Ben-Sahra I, Manning BD . Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 2016; 35: 1250–1260.

    CAS  PubMed  Google Scholar 

  55. Ben-Sahra I, Howell JJ, Asara JM, Manning BD . Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science 2013; 339: 1323–1328.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Robitaille AM, Christen S, Shimobayashi M, Cornu M, Fava LL, Moes S et al. Quantitative phosphoproteomics reveal mTORC1 activates de novo pyrimidine synthesis. Science 2013; 339: 1320–1323.

    CAS  PubMed  Google Scholar 

  57. Ben-Sahra I, Hoxhaj G, Ricoult SJH, Asara JM, Manning BD . mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 2016; 351: 728–733.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 2013; 71: 523–530.

    CAS  PubMed  Google Scholar 

  59. Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B et al. mTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell Elsevier 2016; 29: 548–562.

    CAS  Google Scholar 

  60. Palm W, Park Y, Wright K, Pavlova NN, Tuveson DA, Thompson CB . The utilization of extracellular proteins as nutrients is suppressed by mTORC1. Cell 2015; 162: 259–270.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim YC, Guan K-L . mTOR: a pharmacologic target for autophagy regulation. J Clin Invest 2015; 125: 25–32.

    PubMed  PubMed Central  Google Scholar 

  62. White E . The role for autophagy in cancer. J Clin Invest 2015; 125: 42–46.

    PubMed  PubMed Central  Google Scholar 

  63. Yue Z, Jin S, Yang C, Levine AJ, Heintz N . Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 2003; 100: 15077–15082.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest 2003; 112: 1809–1820.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006; 10: 51–64.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Humphrey SJ, Yang G, Yang P, Fazakerley DJ, Stöckli J, Yang JY et al. Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. Cell Metab 2013; 17: 1009–1020.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang G, Murashige DS, Humphrey SJ, James DE . A positive feedback loop between Akt and mTORC2 via SIN1 phosphorylation. Cell Rep 2015; 12: 937–943.

    CAS  PubMed  Google Scholar 

  69. Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O et al. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 2013; 15: 1340–1350.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhang J, Xu K, Liu P, Geng Y, Wang B, Gan W et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell 2016; 62: 929–942.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B et al. Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance. Cancer Discov 2011; 1: 524–538.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T et al. mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 2013; 18: 726–739.

    CAS  PubMed  Google Scholar 

  74. Gasser JA, Inuzuka H, Lau AW, Wei W, Beroukhim R, Toker A . SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol Cell 2014; 56: 595–607.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S et al. mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proc Natl Acad Sci USA 2014; 111: 409–414.

    CAS  PubMed  Google Scholar 

  76. Sommer EM, Dry H, Cross D, Guichard S, Davies BR, Alessi DR . Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors. Biochem J 2013; 452: 499–508.

    CAS  PubMed  Google Scholar 

  77. Bakker WJ, Harris IS, Mak TW . FOXO3a is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2. Mol Cell 2007; 28: 941–953.

    CAS  PubMed  Google Scholar 

  78. Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ et al. mTOR Directs Breast Morphogenesis through the PKC-alpha-Rac1 Signaling Axis. PLoS Genet 2015; 11: e1005291.

    PubMed  PubMed Central  Google Scholar 

  79. Lee K, Nam KT, Cho SH, Gudapati P, Hwang Y, Park D-S et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med 2012; 209: 713–728.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cheng H, Zou Y, Ross JS, Wang K, Liu X, Halmos B et al. RICTOR amplification defines a novel subset of lung cancer patients who may benefit from treatment with mTOR1/2 inhibitors. Cancer Discov 2015; 5: 1262–1270.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Morrison-Joly M, Hicks DJ, Jones B, Sanchez V, Estrada M V, Young C et al. Rictor/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers. Cancer Res 2016; 76: 4752–4764.

    CAS  PubMed  Google Scholar 

  82. Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 2014; 4: 232–245.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  84. Sarbassov DD, Ali SM, Sengupta S, Sheen J-H, Hsu PP, Bagley AF et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 2006; 22: 159–168.

    CAS  PubMed  Google Scholar 

  85. Benjamin D, Colombi M, Moroni C, Hall MN . Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 2011; 10: 868–880.

    CAS  PubMed  Google Scholar 

  86. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: 2271–2281.

    CAS  PubMed  Google Scholar 

  87. Yu K, Toral-Barza L, Shi C, Zhang W-G, Lucas J, Shor B 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: 6232–6240.

    CAS  PubMed  Google Scholar 

  88. Sun S-Y, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 2005; 65: 7052–7058.

    CAS  PubMed  Google Scholar 

  89. O’Reilly KE, Rojo F, She Q-B, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–1508.

    PubMed  PubMed Central  Google Scholar 

  90. Naing A, Aghajanian C, Raymond E, Olmos D, Schwartz G, Oelmann E et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8055 in advanced solid tumours and lymphoma. Br J Cancer 2012; 107: 1093–1099.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Basu B, Dean E, Puglisi M, Greystoke A, Ong M, Burke W et al. First-in-human pharmacokinetic and pharmacodynamic study of the dual m-TORC 1/2 inhibitor AZD2014. Clin Cancer Res 2015; 21: 3412–3419.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Rodrik-Outmezguine VS, Okaniwa M, Yao Z, Novotny CJ, McWhirter C, Banaji A et al. Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 2016; 534: 272–276.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Britten CD, Adjei AA, Millham R, Houk BE, Borzillo G, Pierce K et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest New Drugs 2014; 32: 510–517.

    CAS  PubMed  Google Scholar 

  94. Jänne PA, Cohen RB, Laird AD, Macé S, Engelman JA, Ruiz-Soto R et al. Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. J Thorac Oncol 2014; 9: 316–323.

    PubMed  Google Scholar 

  95. Viñals F, Chambard JC, Pouysségur J . p70 S6 kinase-mediated protein synthesis is a critical step for vascular endothelial cell proliferation. J Biol Chem 1999; 274: 26776–26782.

    PubMed  Google Scholar 

  96. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128–135.

    CAS  PubMed  Google Scholar 

  97. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F et al. Regulation of hypoxia-inducible factor 1 expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002; 22: 7004–7014.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J et al. PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 2006; 442: 779–785.

    CAS  PubMed  Google Scholar 

  99. Sun S, Chen S, Liu F, Wu H, McHugh J, Bergin IL et al. Constitutive activation of mTORC1 in endothelial cells leads to the development and progression of lymphangiosarcoma through VEGF autocrine signaling. Cancer Cell 2015; 28: 758–772.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M et al. Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol 2015; 35: 1299–1313.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006; 11: 859–871.

    CAS  PubMed  Google Scholar 

  102. Farhan MA, Carmine-Simmen K, Lewis JD, Moore RB, Murray AG . Endothelial cell mTOR complex-2 regulates sprouting angiogenesis. PLoS One 2015; 10: e0135245.

    PubMed  PubMed Central  Google Scholar 

  103. Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W . CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene 2016; 35: 816–826.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhuang G, Yu K, Jiang Z, Chung A, Yao J, Ha C et al. Phosphoproteomic analysis implicates the mTORC2-FoxO1 axis in VEGF signaling and feedback activation of receptor tyrosine kinases. Sci Signal 2013; 6: ra25.

    PubMed  Google Scholar 

  106. Paik J-H, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 2007; 128: 309–323.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Wilhelm K, Happel K, Eelen G, Schoors S, Oellerich MF, Lim R et al. FOXO1 couples metabolic activity and growth state in the vascular endothelium. Nature. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2016, advance on.

  108. Roy D, Sin S-H, Lucas A, Venkataramanan R, Wang L, Eason A et al. mTOR inhibitors block Kaposi sarcoma growth by inhibiting essential autocrine growth factors and tumor angiogenesis. Cancer Res 2013; 73: 2235–2246.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Chatterjee S, Heukamp LC, Siobal M, Schöttle J, Wieczorek C, Peifer M et al. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer. J Clin Invest 2013; 123: 1732–1740.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lane HA, Wood JM, McSheehy PMJ, Allegrini PR, Boulay A, Brueggen J et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 2009; 15: 1612–1622.

    CAS  PubMed  Google Scholar 

  111. Shinohara ET, Cao C, Niermann K, Mu Y, Zeng F, Hallahan DE et al. Enhanced radiation damage of tumor vasculature by mTOR inhibitors. Oncogene 2005; 24: 5414–5422.

    CAS  PubMed  Google Scholar 

  112. Fokas E, Im JH, Hill S, Yameen S, Stratford M, Beech J et al. Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer Res 2012; 72: 239–248.

    CAS  PubMed  Google Scholar 

  113. Sharma P, Allison JP, Curtin JA, Fridlyand J, Kageshita T, Patel HN et al. The future of immune checkpoint therapy. Science 2015; 348: 56–61.

    CAS  PubMed  Google Scholar 

  114. Lastwika KJ, Wilson W, Li QK, Norris J, Xu H, Ghazarian SR et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res 2016; 76: 227–238.

    CAS  PubMed  Google Scholar 

  115. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 2015; 162: 1242–1256.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Granot Z, Fridlender ZG . Plasticity beyond cancer cells and the ‘immunosuppressive switch’. Cancer Res 2015; 75: 4441–4445.

    CAS  PubMed  Google Scholar 

  117. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009; 30: 832–844.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010; 32: 743–753.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Heikamp EB, Patel CH, Collins S, Waickman A, Oh M-H, Sun I-H et al. The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol 2014; 15: 457–464.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Pollizzi KN, Patel CH, Sun I-H, Oh M-H, Waickman AT, Wen J et al. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. J Clin Invest 2015; 125: 2090–2108.

    PubMed  PubMed Central  Google Scholar 

  121. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009; 460: 108–112.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhang L, Tschumi BO, Lopez-Mejia IC, Oberle SG, Meyer M, Samson G et al. Mammalian target of rapamycin complex 2 controls CD8 T cell memory differentiation in a Foxo1-dependent manner. Cell Rep 2016; 14: 1206–1217.

    CAS  PubMed  Google Scholar 

  123. Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 2013; 4: 2834.

    PubMed  Google Scholar 

  124. Lee K, Heffington L, Jellusova J, Nam KT, Raybuck A, Cho SH et al. Requirement for Rictor in homeostasis and function of mature B lymphoid cells. Blood 2013; 122: 2369–2379.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Mateo J, Olmos D, Dumez H, Poondru S, Samberg NL, Barr S et al. A first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies. Br J Cancer 2016; 114: 889–896.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Powles T, Wheater M, Din O, Geldart T, Boleti E, Stockdale A 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: 450–456.

    CAS  PubMed  Google Scholar 

  127. Bendell JC, Kelley RK, Shih KC, Grabowsky JA, Bergsland E, Jones S et al. A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma. Cancer 2015; 121: 3481–3490.

    CAS  PubMed  Google Scholar 

  128. Bendell JC, Kurkjian C, Infante JR, Bauer TM, Burris HA, Greco FA et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs 2015; 33: 463–471.

    CAS  PubMed  Google Scholar 

  129. Seront E, Rottey S, Filleul B, Glorieux P, Goeminne J, Verschaeve V et al. Phase II study of dual phosphoinositol-3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor BEZ235 in patients with locally advanced or metastatic transitional cell carcinoma (TCC). BJU Int 2016; 118: 408–415.

    CAS  PubMed  Google Scholar 

  130. Fazio N, Buzzoni R, Baudin E, Antonuzzo L, Hubner RA, Lahner H et al. A phase II study of BEZ235 in patients with everolimus-resistant, advanced pancreatic neuroendocrine tumours. Anticancer Res 2016; 36: 713–719.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Wen PY, Omuro A, Ahluwalia MS, Fathallah-Shaykh HM, Mohile N, Lager JJ et al. Phase I dose-escalation study of the PI3K/mTOR inhibitor voxtalisib (SAR245409, XL765) plus temozolomide with or without radiotherapy in patients with high-grade glioma. Neuro Oncol 2015; 17: 1275–1283.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Papadopoulos KP, Egile C, Ruiz-Soto R, Jiang J, Shi W, Bentzien F 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: 1763–1770.

    CAS  PubMed  Google Scholar 

  133. Papadopoulos KP, Tabernero J, Markman B, Patnaik A, Tolcher AW, Baselga J et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245409 (XL765), a novel, orally administered PI3K/mTOR inhibitor in patients with advanced solid tumors. Clin Cancer Res 2014; 20: 2445–2456.

    CAS  PubMed  Google Scholar 

  134. Dolly SO, Wagner AJ, Bendell JC, Kindler HL, Krug LM, Seiwert TY et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2016; 22: 2874–2884.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Powles T, Lackner MR, Oudard S, Escudier B, Ralph C, Brown JE et al. Randomized open-label phase II trial of apitolisib (GDC-0980), a novel inhibitor of the PI3K/mammalian target of rapamycin pathway, versus everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2016; 34: 1660–1668.

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res 2015; 21: 1888–1895.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Munster P, Aggarwal R, Hong D, Schellens JHM, van der Noll R, Specht J et al. First-in-human phase I study of GSK2126458, an oral pan-class I phosphatidylinositol-3-kinase inhibitor, in patients with advanced solid tumor malignancies. Clin Cancer Res 2015; 22: 1932–1939.

    PubMed  Google Scholar 

  138. Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A, Gore M et al. A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol 2016; 142: 62–69.

    CAS  PubMed  Google Scholar 

  139. Mahadevan D, Chiorean EG, Harris WB, Von Hoff DD, Stejskal-Barnett A, Qi W et al. Phase I pharmacokinetic and pharmacodynamic study of the pan-PI3K/mTORC vascular targeted pro-drug SF1126 in patients with advanced solid tumours and B-cell malignancies. Eur J Cancer 2012; 48: 3319–3327.

    CAS  PubMed  Google Scholar 

  140. Markman B, Tabernero J, Krop I, Shapiro GI, Siu L, Chen LC et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of the oral phosphatidylinositol-3-kinase and mTOR inhibitor BGT226 in patients with advanced solid tumors. Ann Oncol 2012; 23: 2399–2408.

    CAS  PubMed  Google Scholar 

  141. LaGory EL, Giaccia AJ . The ever-expanding role of HIF in tumour and stromal biology. Nat Cell Biol 2016; 18: 356–365.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Mayerhofer M, Valent P, Sperr WR, Griffin JD, Sillaber C . BCR/ABL induces expression of vascular endothelial growth factor and its transcriptional activator, hypoxia inducible factor-1alpha, through a pathway involving phosphoinositide 3-kinase and the mammalian target of rapamycin. Blood 2002; 100: 3767–3775.

    CAS  PubMed  Google Scholar 

  143. Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG . TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 2003; 4: 147–158.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Deanna Edwards for careful review of the manuscript. This work was supported by the Department of Veterans Affairs through a VA Merit Award and a Research Career Scientist Award (J Chen), NIH grants R01 CA95004 and R01 CA177681 (J Chen) and T-32 CA009592 (L Kim).

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Kim, L., Cook, R. & Chen, J. mTORC1 and mTORC2 in cancer and the tumor microenvironment. Oncogene 36, 2191–2201 (2017). https://doi.org/10.1038/onc.2016.363

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