MTORC1 and mTORC2 in cancer and the tumor microenvironment

Oncogene

Volumn 36, Issue 16, 2017, Pages 2191-2201

  Kim, L C ^a   Cook, R S ^a,b   Chen, J ^a,b,c,d  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b VANDERBILT INGRAM CANCER CENTER   (United States)

^c VANDERBILT UNIVERSITY   (United States)

^d VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 2; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MECHANISTIC TARGET OF RAPAMYCIN COMPLEX 1; MULTIPROTEIN COMPLEX; TARGET OF RAPAMYCIN KINASE; TOR COMPLEX 2;

BLOOD VESSEL; CANCER THERAPY; DIABETES MELLITUS; GENOMICS; HUMAN; MALIGNANT NEOPLASM; NERVE DEGENERATION; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; VASCULARIZATION; ANIMAL; METABOLISM; NEOPLASM;

ANIMALS; HUMANS; MULTIPROTEIN COMPLEXES; NEOPLASMS; TOR SERINE-THREONINE KINASES; TUMOR MICROENVIRONMENT;

EID: 84991687314     PISSN: 09509232     EISSN: 14765594     Source Type: Journal    
DOI: 10.1038/onc.2016.363     Document Type: Review

References (138)

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
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
3. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144: 646-674
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
5. Jacinto E, Loewith R, Schmidt A, Lin S, Röegg MA, Hall A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6: 1122-1128
6. Laplante M, Sabatini DM. mTOR signaling in growth control and disease Cell 2012; 149: 274-293
7. Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP. mTOR kinase structure, mechanism and regulation. Nature 2013; 497: 217-223
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
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
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
11. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011; 144: 757-768
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
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
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
15. Potter CJ, Pedraza LG, Xu T. Akt regulates growth by directly phosphorylating Tsc2 Nat Cell Biol 2002; 4: 658-665
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
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
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
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
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
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
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
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
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
25. Inoki K, Zhu T, Guan K-L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577-590
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
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
28. Shimobayashi M, Hall MN. Multiple amino acid sensing inputs to mTORC1 Cell Res 2016; 26: 7-20
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
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
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
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
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
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
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
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
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
38. Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control Nat Rev Mol Cell Biol 2009; 10: 307-318
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
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
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
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
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
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
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
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
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
48. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D et al. The mTORregulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 2011; 332: 1317-1322
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
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
51. Dövel 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
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
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
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
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
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
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
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
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
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
61. Kim YC, Guan K-L. mTOR: A pharmacologic target for autophagy regulation J Clin Invest 2015; 125: 25-32
62. White E. The role for autophagy in cancer. J Clin Invest 2015; 125: 42-46
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
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
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
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
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
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
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
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
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
72. Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B et al. Oncogenic EGFR signaling activates an mTORC2-NF-KB pathway that promotes chemotherapy resistance. Cancer Discov 2011; 1: 524-538
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
89. OReilly 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
116. Granot Z, Fridlender ZG. Plasticity beyond cancer cells and the immunosuppressive switch. Cancer Res 2015; 75: 4441-4445
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
136. Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL et al. First-inhuman 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
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
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