{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T11:49:20Z","timestamp":1778759360549,"version":"3.51.4"},"reference-count":235,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2012,2,10]],"date-time":"2012-02-10T00:00:00Z","timestamp":1328832000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The conserved serine\/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K\/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-\u03b1 and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification\/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.<\/jats:p>","DOI":"10.3390\/ijms13021886","type":"journal-article","created":{"date-parts":[[2012,2,10]],"date-time":"2012-02-10T11:23:18Z","timestamp":1328872998000},"page":"1886-1918","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":692,"title":["The mTOR Signalling Pathway in Human Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"Helena","family":"P\u00f3pulo","sequence":"first","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), University of Porto, 4200-465, Porto, Portugal"},{"name":"Medical Faculty, University of Porto, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8597-3474","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Lopes","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), University of Porto, 4200-465, Porto, Portugal"},{"name":"Medical Faculty, University of Porto, 4200-465 Porto, Portugal"},{"name":"Department of Pathology, Hospital S\u00e3o Jo\u00e3o, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9607-6998","authenticated-orcid":false,"given":"Paula","family":"Soares","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathology and Immunology of University of Porto (IPATIMUP), University of Porto, 4200-465, Porto, Portugal"},{"name":"Medical Faculty, University of Porto, 4200-465 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2012,2,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/S1471-4892(03)00071-7","article-title":"Targeting mTOR signaling for cancer therapy","volume":"3","author":"Huang","year":"2003","journal-title":"Curr. Opin. Pharmacol"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ccr.2007.05.008","article-title":"Defining the role of mTOR in cancer","volume":"12","author":"Guertin","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1126\/science.1715094","article-title":"Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast","volume":"253","author":"Heitman","year":"1991","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1074\/jbc.270.2.815","article-title":"Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells","volume":"270","author":"Sabers","year":"1995","journal-title":"J. Biol. Chem"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0092-8674(94)90570-3","article-title":"RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs","volume":"78","author":"Sabatini","year":"1994","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/369756a0","article-title":"A mammalian protein targeted by G1-arresting rapamycin-receptor complex","volume":"369","author":"Brown","year":"1994","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1126\/science.270.5233.50","article-title":"PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints","volume":"270","author":"Keith","year":"1995","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0092-8674(93)90144-F","article-title":"Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression","volume":"73","author":"Kunz","year":"1993","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2174\/138920310791824093","article-title":"The complexes of mammalian target of rapamycin","volume":"11","author":"Zhou","year":"2010","journal-title":"Curr. Protein Pept. Sci"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/S1097-2765(02)00636-6","article-title":"Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control","volume":"10","author":"Loewith","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.cub.2004.06.054","article-title":"Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton","volume":"14","author":"Sarbassov","year":"2004","journal-title":"Curr. Biol"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S0092-8674(02)00833-4","article-title":"Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action","volume":"110","author":"Hara","year":"2002","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0092-8674(02)00808-5","article-title":"mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery","volume":"110","author":"Kim","year":"2002","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/j.molcel.2007.03.003","article-title":"PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase","volume":"25","author":"Sancak","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2009.03.046","article-title":"DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival","volume":"137","author":"Peterson","year":"2009","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.molcel.2008.03.003","article-title":"AMPK phosphorylation of raptor mediates a metabolic checkpoint","volume":"30","author":"Gwinn","year":"2008","journal-title":"Mol Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/S1097-2765(03)00114-X","article-title":"G\u03b2L, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR","volume":"11","author":"Kim","year":"2003","journal-title":"Mol. Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.devcel.2006.10.007","article-title":"Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC\u03b1, but not S6K1","volume":"11","author":"Guertin","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.1182\/blood-2006-06-030833","article-title":"Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML","volume":"109","author":"Zeng","year":"2007","journal-title":"Blood"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes Dev"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1093\/embo-reports\/kvf197","article-title":"The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase","volume":"3","author":"Choi","year":"2002","journal-title":"EMBO Rep"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1002\/j.1460-2075.1996.tb00582.x","article-title":"Regulation of translation elongation factor-2 by insulin via a rapamycin-sensitive signalling pathway","volume":"15","author":"Redpath","year":"1996","journal-title":"EMBO J"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/sj.bjp.0700936","article-title":"Inhibition by rapamycin of ornithine decarboxylase and epithelial cell proliferation in intestinal IEC-6 cells in culture","volume":"120","author":"Seidel","year":"1997","journal-title":"Br. J. Pharmacol"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5033","DOI":"10.1074\/jbc.271.9.5033","article-title":"Regulation of both glycogen synthase and PHAS-I by insulin in rat skeletal muscle involves mitogen-activated protein kinase-independent and rapamycin-sensitive pathways","volume":"271","author":"Azpiazu","year":"1996","journal-title":"J. Biol. Chem"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7004","DOI":"10.1128\/MCB.22.20.7004-7014.2002","article-title":"Regulation of hypoxia-inducible factor 1\u03b1 expression and function by the mammalian target of rapamycin","volume":"22","author":"Hudson","year":"2002","journal-title":"Mol. Cell Biol"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1073\/pnas.022634399","article-title":"Insulin-stimulated phosphorylation of lipin mediated by the mammalian target of rapamycin","volume":"99","author":"Huffman","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"34758","DOI":"10.1074\/jbc.274.49.34758","article-title":"Mammalian TOR controls one of two kinase pathways acting upon nPKC\u03b4 and nPKC\u025b","volume":"274","author":"Parekh","year":"1999","journal-title":"J. Biol. Chem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4438","DOI":"10.1073\/pnas.96.8.4438","article-title":"Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein","volume":"96","author":"Peterson","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","first-page":"3373","article-title":"p53\/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin","volume":"61","author":"Huang","year":"2001","journal-title":"Cancer Res"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/372570a0","article-title":"Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin","volume":"372","author":"Nourse","year":"1994","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1006\/bbrc.2000.3201","article-title":"Retinoblastoma protein phosphorylation via PI 3-kinase and mTOR pathway regulates adipocyte differentiation","volume":"275","author":"Usui","year":"2000","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0960-9822(99)00268-7","article-title":"Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR","volume":"10","author":"Yokogami","year":"2000","journal-title":"Curr. Biol"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/ncb1183","article-title":"Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive","volume":"6","author":"Jacinto","year":"2004","journal-title":"Nat. Cell Biol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/j.cub.2006.08.001","article-title":"mSin1 is necessary for Akt\/PKB phosphorylation, and its isoforms define three distinct mTORC2s","volume":"16","author":"Frias","year":"2006","journal-title":"Curr. Biol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1042\/BJ20070540","article-title":"Identification of Protor as a novel Rictor-binding component of mTOR complex-2","volume":"405","author":"Pearce","year":"2007","journal-title":"Biochem. J"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.bbrc.2008.05.086","article-title":"Hsp70 associates with Rictor and is required for mTORC2 formation and activity","volume":"372","author":"Martin","year":"2008","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"40406","DOI":"10.1074\/jbc.M508361200","article-title":"mTOR.RICTOR is the Ser473 kinase for Akt\/protein kinase B in 3T3-L1 adipocytes","volume":"280","author":"Hresko","year":"2005","journal-title":"J. Biol. Chem"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2006.03.029","article-title":"Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt\/PKB","volume":"22","author":"Sarbassov","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.cmet.2006.05.003","article-title":"Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1","volume":"3","author":"Um","year":"2006","journal-title":"Cell Metab"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0960-9822(06)00122-9","article-title":"Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B\u03b1","volume":"7","author":"Alessi","year":"1997","journal-title":"Curr. Biol"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1126\/science.277.5325.567","article-title":"Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B","volume":"277","author":"Stokoe","year":"1997","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0092-8674(00)81780-8","article-title":"Negative regulation of PKB\/Akt-dependent cell survival by the tumor suppressor PTEN","volume":"95","author":"Stambolic","year":"1998","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat. Cell Biol"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1101\/gad.1110003","article-title":"Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling","volume":"17","author":"Inoki","year":"2003","journal-title":"Genes Dev"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cub.2005.02.053","article-title":"Rheb binds and regulates the mTOR kinase","volume":"15","author":"Long","year":"2005","journal-title":"Curr. Biol"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"32768","DOI":"10.1074\/jbc.M506280200","article-title":"Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase\/mTOR pathway","volume":"280","author":"Takahashi","year":"2005","journal-title":"J. Biol. Chem"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.bbrc.2006.03.220","article-title":"Localization of Rheb to the endomembrane is critical for its signaling function","volume":"344","author":"Buerger","year":"2006","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10189","DOI":"10.1074\/jbc.M210837200","article-title":"Identification of a proline-rich Akt substrate as a 14-3-3 binding partner","volume":"278","author":"Kovacina","year":"2003","journal-title":"J Biol Chem"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"45117","DOI":"10.1074\/jbc.M303789200","article-title":"Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway","volume":"278","author":"Lim","year":"2003","journal-title":"J. Biol. Chem"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"15461","DOI":"10.1074\/jbc.C200665200","article-title":"The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif","volume":"278","author":"Nojima","year":"2003","journal-title":"J. Biol. Chem"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S0960-9822(03)00329-4","article-title":"TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function","volume":"13","author":"Schalm","year":"2003","journal-title":"Curr. Biol"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/S0960-9822(02)00762-5","article-title":"Identification of a conserved motif required for mTOR signaling","volume":"12","author":"Schalm","year":"2002","journal-title":"Curr. Biol"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6242","DOI":"10.1128\/MCB.16.11.6242","article-title":"The principal rapamycin-sensitive p70(s6k) phosphorylation sites, T-229 and T-389, are differentially regulated by rapamycin-insensitive kinase kinases","volume":"16","author":"Dennis","year":"1996","journal-title":"Mol. Cell Biol"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nrd2062","article-title":"Current development of mTOR inhibitors as anticancer agents","volume":"5","author":"Faivre","year":"2006","journal-title":"Nat. Rev. Drug Discov"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/S0955-0674(98)80150-6","article-title":"The mRNA 5\u2032 cap-binding protein eIF4E and control of cell growth","volume":"10","author":"Sonenberg","year":"1998","journal-title":"Curr. Opin. Cell Biol"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1038\/371762a0","article-title":"Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5\u2032-cap function","volume":"371","author":"Pause","year":"1994","journal-title":"Nature"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1080\/08977190701779101","article-title":"Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function","volume":"25","author":"Jastrzebski","year":"2007","journal-title":"Growth Factors"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins","volume":"166","author":"Harrington","year":"2004","journal-title":"J. Cell Biol"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.cub.2004.08.026","article-title":"Inappropriate activation of the TSC\/Rheb\/mTOR\/S6K cassette induces IRS1\/2 depletion, insulin resistance, and cell survival deficiencies","volume":"14","author":"Shah","year":"2004","journal-title":"Curr. Biol"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.tibs.2003.09.003","article-title":"Rheb fills a GAP between TSC and TOR","volume":"28","author":"Manning","year":"2003","journal-title":"Trends Biochem. Sci"},{"key":"ref_63","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo","year":"2008","journal-title":"J. Clin. Invest"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/ncb1547","article-title":"Insulin signalling to mTOR mediated by the Akt\/PKB substrate PRAS40","volume":"9","author":"Lee","year":"2007","journal-title":"Nat. Cell Biol"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/nrg1879","article-title":"The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism","volume":"7","author":"Engelman","year":"2006","journal-title":"Nat. Rev. Genet"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1016\/j.febslet.2006.04.068","article-title":"The amino acid sensitive TOR pathway from yeast to mammals","volume":"580","author":"Dann","year":"2006","journal-title":"FEBS Lett"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"227S","DOI":"10.1093\/jn\/136.1.227S","article-title":"Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis","volume":"136","author":"Kimball","year":"2006","journal-title":"J. Nutr"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"14238","DOI":"10.1073\/pnas.0506925102","article-title":"Amino acids mediate mTOR\/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase","volume":"102","author":"Nobukuni","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"33076","DOI":"10.1074\/jbc.M507201200","article-title":"hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase","volume":"280","author":"Byfield","year":"2005","journal-title":"J. Biol. Chem"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","article-title":"TSC2 mediates cellular energy response to control cell growth and survival","volume":"115","author":"Inoki","year":"2003","journal-title":"Cell"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"32081","DOI":"10.1074\/jbc.M502876200","article-title":"Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity","volume":"280","author":"Nogueira","year":"2005","journal-title":"J. Biol. Chem"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1128\/MCB.25.14.5834-5845.2005","article-title":"Regulation of mTOR and cell growth in response to energy stress by REDD1","volume":"25","author":"Sofer","year":"2005","journal-title":"Mol. Cell Biol"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2893","DOI":"10.1101\/gad.1256804","article-title":"Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1\/TSC2 tumor suppressor complex","volume":"18","author":"Brugarolas","year":"2004","journal-title":"Genes Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1128\/MCB.22.7.2283-2293.2002","article-title":"Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis","volume":"22","author":"Shoshani","year":"2002","journal-title":"Mol. Cell Biol"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.molcel.2006.01.010","article-title":"Hypoxia-induced energy stress regulates mRNA translation and cell growth","volume":"21","author":"Liu","year":"2006","journal-title":"Mol. Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/S0959-437X(99)80016-1","article-title":"Ras caught in another affair: The exchange factors for Ral","volume":"9","author":"Wolthuis","year":"1999","journal-title":"Curr. Opin. Genet. Dev"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.tcb.2004.09.014","article-title":"Renewing the conspiracy theory debate: Does Raf function alone to mediate Ras oncogenesis?","volume":"14","author":"Repasky","year":"2004","journal-title":"Trends Cell Biol"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1038\/sj.onc.1210422","article-title":"Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer","volume":"26","author":"Roberts","year":"2007","journal-title":"Oncogene"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.gde.2006.12.004","article-title":"Deregulated Ras signaling in developmental disorders: New tricks for an old dog","volume":"17","author":"Schubbert","year":"2007","journal-title":"Curr. Opin. Genet. Dev"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1073\/pnas.0409143102","article-title":"Quantitative phosphorylation profiling of the ERK\/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors","volume":"102","author":"Ballif","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.cell.2005.02.031","article-title":"Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis","volume":"121","author":"Ma","year":"2005","journal-title":"Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"7106","DOI":"10.1158\/0008-5472.CAN-06-4798","article-title":"Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer","volume":"67","author":"Ma","year":"2007","journal-title":"Cancer Res"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"4258","DOI":"10.2741\/3003","article-title":"The RSK factors of activating the Ras\/MAPK signaling cascade","volume":"13","author":"Carriere","year":"2008","journal-title":"Front. Biosci"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1093\/emboj\/18.1.270","article-title":"Human eukaryotic translation initiation factor 4G (eIF4G) recruits mnk1 to phosphorylate eIF4E","volume":"18","author":"Pyronnet","year":"1999","journal-title":"EMBO J"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1128\/MCB.21.3.743-754.2001","article-title":"The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells","volume":"21","author":"Scheper","year":"2001","journal-title":"Mol. Cell Biol"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.1073\/pnas.051042298","article-title":"A phosphatidylinositol 3-kinase\/Akt\/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1","volume":"98","author":"Ozes","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1038\/sj.cdd.4401285","article-title":"M-CSF, TNF\u03b1 and RANK ligand promote osteoclast survival by signaling through mTOR\/S6 kinase","volume":"10","author":"Glantschnig","year":"2003","journal-title":"Cell Death Differ"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.cell.2007.05.058","article-title":"IKK \u03b2 suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway","volume":"130","author":"Lee","year":"2007","journal-title":"Cell"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1046\/j.1440-1711.1999.00800.x","article-title":"Signalling by CD95 and TNF receptors: Not only life and death","volume":"77","author":"Magnusson","year":"1999","journal-title":"Immunol. Cell Biol"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/cr.2008.30","article-title":"The I\u03baB kinase\u2014a bridge between inflammation and cancer","volume":"18","author":"Karin","year":"2008","journal-title":"Cell Res"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7582","DOI":"10.4049\/jimmunol.180.11.7582","article-title":"Differential involvement of I\u03baB kinases \u03b1 and \u03b2 in cytokine- and insulin-induced mammalian target of rapamycin activation determined by Akt","volume":"180","author":"Dan","year":"2008","journal-title":"J. Immunol"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.cell.2006.08.033","article-title":"SIN1\/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity","volume":"127","author":"Jacinto","year":"2006","journal-title":"Cell"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1128\/MCB.00289-08","article-title":"The TSC1-TSC2 complex is required for proper activation of mTOR complex 2","volume":"28","author":"Huang","year":"2008","journal-title":"Mol. Cell Biol"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"14056","DOI":"10.1073\/pnas.0706517104","article-title":"Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance","volume":"104","author":"Tremblay","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.1101\/gad.845700","article-title":"Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin","volume":"14","author":"Oldham","year":"2000","journal-title":"Genes Dev"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1472","DOI":"10.1101\/gad.995802","article-title":"Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1\/eIF4E","volume":"16","author":"Fingar","year":"2002","journal-title":"Genes Dev"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1038\/sj.emboj.7600384","article-title":"Genome-wide lethality screen identifies new PI4,5P2 effectors that regulate the actin cytoskeleton","volume":"23","author":"Audhya","year":"2004","journal-title":"EMBO J"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1091\/mbc.e04-07-0564","article-title":"The pleckstrin homology domain proteins Slm1 and Slm2 are required for actin cytoskeleton organization in yeast and bind phosphatidylinositol-4,5-bisphosphate and TORC2","volume":"16","author":"Fadri","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5575","DOI":"10.1128\/MCB.22.15.5575-5584.2002","article-title":"The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino acid and glucose deprivation","volume":"22","author":"Peng","year":"2002","journal-title":"Mol. Cell Biol"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"8862","DOI":"10.1128\/MCB.23.23.8862-8877.2003","article-title":"mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF","volume":"23","author":"Hannan","year":"2003","journal-title":"Mol. Cell Biol"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1101\/gad.285504","article-title":"mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability","volume":"18","author":"Mayer","year":"2004","journal-title":"Genes Dev"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"33637","DOI":"10.1074\/jbc.M301053200","article-title":"Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene transcription by lipopolysaccharide and interferon-gamma is regulated by mammalian target of rapamycin","volume":"278","author":"Kristof","year":"2003","journal-title":"J. Biol. Chem"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3271","DOI":"10.1101\/gad.13.24.3271","article-title":"The TOR signaling cascade regulates gene expression in response to nutrients","volume":"13","author":"Cardenas","year":"1999","journal-title":"Genes Dev"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"14866","DOI":"10.1073\/pnas.96.26.14866","article-title":"Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins","volume":"96","author":"Hardwick","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1091\/mbc.10.4.987","article-title":"Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae","volume":"10","author":"Powers","year":"1999","journal-title":"Mol. Biol. Cell"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/nature06639","article-title":"Autophagy fights disease through cellular self-digestion","volume":"451","author":"Mizushima","year":"2008","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/S1534-5807(04)00099-1","article-title":"Development by self-digestion: Molecular mechanisms and biological functions of autophagy","volume":"6","author":"Levine","year":"2004","journal-title":"Dev. Cell"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1158\/0008-5472.CAN-05-1554","article-title":"Elongation factor-2 kinase regulates autophagy in human glioblastoma cells","volume":"66","author":"Wu","year":"2006","journal-title":"Cancer Res"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/nature09076","article-title":"Termination of autophagy and reformation of lysosomes regulated by mTOR","volume":"465","author":"Yu","year":"2010","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.semcdb.2004.11.005","article-title":"mTOR, translational control and human disease","volume":"16","author":"Tee","year":"2005","journal-title":"Semin. Cell Dev. Biol"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"8351","DOI":"10.1158\/1078-0432.CCR-04-0130","article-title":"Antibody-based profiling of the phosphoinositide 3-kinase pathway in clinical prostate cancer","volume":"10","author":"Thomas","year":"2004","journal-title":"Clin. Cancer Res"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.2337\/diabetes.53.11.2748","article-title":"regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis","volume":"53","author":"Kim","year":"2004","journal-title":"Diabetes"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.biochi.2004.10.021","article-title":"PPAR gamma, 10 years later","volume":"87","author":"Lazar","year":"2005","journal-title":"Biochimie"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nature02866","article-title":"Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity","volume":"431","author":"Um","year":"2004","journal-title":"Nature"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.ceb.2005.02.008","article-title":"The expanding TOR signaling network","volume":"17","author":"Martin","year":"2005","journal-title":"Curr. Opin. Cell Biol"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1126\/science.1173635","article-title":"Caloric restriction delays disease onset and mortality in rhesus monkeys","volume":"325","author":"Colman","year":"2009","journal-title":"Science"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nature08221","article-title":"Rapamycin fed late in life extends lifespan in genetically heterogeneous mice","volume":"460","author":"Harrison","year":"2009","journal-title":"Nature"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1038\/onc.2010.28","article-title":"Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer","volume":"29","author":"Sato","year":"2010","journal-title":"Oncogene"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"8027","DOI":"10.1074\/jbc.275.11.8027","article-title":"HER-2\/neu blocks tumor necrosis factor-induced apoptosis via the Akt\/NF-\u03baB pathway","volume":"275","author":"Zhou","year":"2000","journal-title":"J. Biol. Chem"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1083\/jcb.200112015","article-title":"Integrin (\u03b16\u03b24) regulation of eIF-4E activity and VEGF translation: A survival mechanism for carcinoma cells","volume":"158","author":"Chung","year":"2002","journal-title":"J. Cell Biol"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"6084","DOI":"10.1158\/0008-5472.CAN-07-6854","article-title":"An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer","volume":"68","author":"Lluch","year":"2008","journal-title":"Cancer Res"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1200\/JCO.2004.02.141","article-title":"The biology and clinical relevance of the PTEN tumor suppressor pathway","volume":"22","author":"Sansal","year":"2004","journal-title":"J. Clin. Oncol"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"4071","DOI":"10.1242\/jcs.015230","article-title":"New insights into PTEN","volume":"120","author":"Tamguney","year":"2007","journal-title":"J. Cell Sci"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/nrc839","article-title":"The phosphatidylinositol 3-Kinase AKT pathway in human cancer","volume":"2","author":"Vivanco","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"7551","DOI":"10.1158\/0008-5472.CAN-07-0881","article-title":"4E-binding protein 1: A key molecular \u201cfunnel factor\u201d in human cancer with clinical implications","volume":"67","author":"Armengol","year":"2007","journal-title":"Cancer Res"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/sj.bjc.6605044","article-title":"Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity","volume":"100","author":"Coleman","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ygyno.2010.12.364","article-title":"Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer","volume":"121","author":"No","year":"2011","journal-title":"Gynecol. Oncol"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.ccr.2004.05.027","article-title":"Lost in translation: Dysregulation of cap-dependent translation and cancer","volume":"5","author":"Bjornsti","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/nm1042","article-title":"The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis","volume":"10","author":"Ruggero","year":"2004","journal-title":"Nat. Med"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1126\/science.275.5308.1943","article-title":"PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer","volume":"275","author":"Li","year":"1997","journal-title":"Science"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"7678","DOI":"10.1158\/0008-5472.CAN-04-2933","article-title":"Mutation of the PIK3CA gene in ovarian and breast cancer","volume":"64","author":"Campbell","year":"2004","journal-title":"Cancer Res"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth","volume":"441","author":"Shaw","year":"2006","journal-title":"Nature"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"31101","DOI":"10.1074\/jbc.M503763200","article-title":"The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity","volume":"280","author":"Basso","year":"2005","journal-title":"J. Biol. Chem"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"3287","DOI":"10.1158\/0008-5472.CAN-09-3467","article-title":"Mammalian target of rapamycin activator RHEB is frequently overexpressed in human carcinomas and is critical and sufficient for skin epithelial carcinogenesis","volume":"70","author":"Lu","year":"2010","journal-title":"Cancer Res"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1093\/jnci\/92.15.1252","article-title":"Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis","volume":"92","author":"Barlund","year":"2000","journal-title":"J. Natl. Cancer Inst"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/j.1755-148X.2010.00796.x","article-title":"mTOR pathway activation in cutaneous melanoma is associated with poorer prognosis characteristics","volume":"24","author":"Populo","year":"2011","journal-title":"Pigment Cell Melanoma Res"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.lungcan.2010.01.001","article-title":"Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of KRAS and EGFR mutations","volume":"70","author":"Hiramatsu","year":"2010","journal-title":"Lung Cancer"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s10549-007-9746-x","article-title":"Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables","volume":"110","author":"Noh","year":"2008","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1002\/cncr.22677","article-title":"Prognostic relevance of the mTOR pathway in renal cell carcinoma: Implications for molecular patient selection for targeted therapy","volume":"109","author":"Pantuck","year":"2007","journal-title":"Cancer"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s12032-009-9201-4","article-title":"The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma","volume":"27","author":"Zhou","year":"2010","journal-title":"Med. Oncol"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ng1494","article-title":"Dysregulation of the TSC-mTOR pathway in human disease","volume":"37","author":"Inoki","year":"2005","journal-title":"Nat. Genet"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/annonc\/mdi113","article-title":"mTOR-targeted therapy of cancer with rapamycin derivatives","volume":"16","author":"Vignot","year":"2005","journal-title":"Ann. Oncol"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1080\/00313020701570012","article-title":"PTEN expression in renal cell carcinoma and oncocytoma and prognosis","volume":"39","author":"Hager","year":"2007","journal-title":"Pathology"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1111\/j.1755-148X.2009.00585.x","article-title":"The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma","volume":"22","author":"Madhunapantula","year":"2009","journal-title":"Pigment Cell Melanoma Res"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1055\/s-2002-25298","article-title":"Lymphangioleiomyomatosis","volume":"23","author":"Johnson","year":"2002","journal-title":"Semin. Respir. Crit. Care Med"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1046\/j.1469-1809.2003.00012.x","article-title":"Tuberous sclerosis: From tubers to mTOR","volume":"67","author":"Kwiatkowski","year":"2003","journal-title":"Ann. Hum. Genet"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1042\/bst0310573","article-title":"United at last: The tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase\/Akt pathway to mammalian target of rapamycin (mTOR) signalling","volume":"31","author":"Manning","year":"2003","journal-title":"Biochem. Soc. Trans"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1038\/sj.onc.1207545","article-title":"eIF-4E expression and its role in malignancies and metastases","volume":"23","author":"Graff","year":"2004","journal-title":"Oncogene"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"6516","DOI":"10.1158\/0008-5472.CAN-07-6188","article-title":"S6K1 plays a key role in glial transformation","volume":"68","author":"Nakamura","year":"2008","journal-title":"Cancer Res"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/ng0597-64","article-title":"Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome","volume":"16","author":"Liaw","year":"1997","journal-title":"Nat. Genet"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ccr.2004.06.007","article-title":"The LKB1 tumor suppressor negatively regulates mTOR signaling","volume":"6","author":"Shaw","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"8573","DOI":"10.1073\/pnas.0503224102","article-title":"The NF1 tumor suppressor critically regulates TSC2 and mTOR","volume":"102","author":"Johannessen","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/j.1600-0463.2007.apm_855.xml.x","article-title":"The genome and epigenome of malignant melanoma","volume":"115","author":"Dahl","year":"2007","journal-title":"Apmis"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1200\/JCO.2005.07.168","article-title":"Prognostic significance of activated Akt expression in melanoma: A clinicopathologic study of 292 cases","volume":"23","author":"Dai","year":"2005","journal-title":"J. Clin. Oncol"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1038\/sj.onc.1206451","article-title":"PTEN signaling pathways in melanoma","volume":"22","author":"Wu","year":"2003","journal-title":"Oncogene"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s004280050477","article-title":"Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas","volume":"436","author":"Reifenberger","year":"2000","journal-title":"Virchows Arch"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1136\/jmg.37.9.653","article-title":"Identification of PTEN mutations in metastatic melanoma specimens","volume":"37","author":"Celebi","year":"2000","journal-title":"J. Med. Genet"},{"key":"ref_160","first-page":"1800","article-title":"Relative reciprocity of NRAS and PTEN\/MMAC1 alterations in cutaneous melanoma cell lines","volume":"60","author":"Tsao","year":"2000","journal-title":"Cancer Res"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1046\/j.0022-202X.2004.22243.x","article-title":"Genetic interaction between NRAS and BRAF mutations and PTEN\/MMAC1 inactivation in melanoma","volume":"122","author":"Tsao","year":"2004","journal-title":"J. Invest. Dermatol"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1038\/sj.bjc.6604637","article-title":"A novel AKT3 mutation in melanoma tumours and cell lines","volume":"99","author":"Davies","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_163","first-page":"7335","article-title":"Constitutive activation of Akt\/protein kinase B in melanoma leads to up-regulation of nuclear factor-\u03baB and tumor progression","volume":"62","author":"Dhawan","year":"2002","journal-title":"Cancer Res"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"7002","DOI":"10.1158\/0008-5472.CAN-04-1399","article-title":"Deregulated Akt3 activity promotes development of malignant melanoma","volume":"64","author":"Stahl","year":"2004","journal-title":"Cancer Res"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.2741\/1755","article-title":"The RAS\/RAF\/MEK\/ERK and PI3K\/AKT signaling pathways present molecular targets for the effective treatment of advanced melanoma","volume":"10","author":"Meier","year":"2005","journal-title":"Front. Biosci"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"3429","DOI":"10.1158\/0008-5472.CAN-07-5867","article-title":"Akt3 and mutant V600EB-Raf cooperate to promote early melanoma development","volume":"68","author":"Cheung","year":"2008","journal-title":"Cancer Res"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"3626","DOI":"10.1158\/0008-5472.CAN-06-4234","article-title":"PRAS40 deregulates apoptosis in malignant melanoma","volume":"67","author":"Madhunapantula","year":"2007","journal-title":"Cancer Res"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1097\/00008390-200508000-00003","article-title":"Immunohistochemical expression of phospho-Akt in uveal melanoma","volume":"15","author":"Saraiva","year":"2005","journal-title":"Melanoma Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1097\/CMR.0b013e32832ccd09","article-title":"Evaluation of the mTOR pathway in ocular (uvea and conjunctiva) melanoma","volume":"20","author":"Populo","year":"2010","journal-title":"Melanoma Res"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1200\/JCO.2005.02.2418","article-title":"High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma","volume":"24","author":"Yang","year":"2006","journal-title":"J. Clin. Oncol"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/ijc.11064","article-title":"Farnesyl transferase inhibitor SCH66336 is cytostatic, pro-apoptotic and enhances chemosensitivity to cisplatin in melanoma cells","volume":"105","author":"Smalley","year":"2003","journal-title":"Int. J. Cancer"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"6436","DOI":"10.1038\/sj.onc.1209886","article-title":"mTOR and cancer therapy","volume":"25","author":"Easton","year":"2006","journal-title":"Oncogene"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7164\/antibiotics.28.721","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle","volume":"28","author":"Vezina","year":"1975","journal-title":"J. Antibiot. (Tokyo)"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.7164\/antibiotics.37.1231","article-title":"Activity of rapamycin (AY-22,989) against transplanted tumors","volume":"37","author":"Eng","year":"1984","journal-title":"J. Antibiot. (Tokyo)"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0041-1345(03)00328-2","article-title":"Simultaneous pancreas-kidney transplantation initial experience","volume":"35","author":"Linhares","year":"2003","journal-title":"Transplant. Proc"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1023\/A:1013167315885","article-title":"Resistance to rapamycin: A novel anticancer drug","volume":"20","author":"Huang","year":"2001","journal-title":"Cancer Metastasis Rev"},{"key":"ref_177","first-page":"903","article-title":"Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor","volume":"54","author":"Dilling","year":"1994","journal-title":"Cancer Res"},{"key":"ref_178","first-page":"1527","article-title":"Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor\/medulloblastoma models as single agent and in combination chemotherapy","volume":"61","author":"Geoerger","year":"2001","journal-title":"Cancer Res"},{"key":"ref_179","first-page":"3895","article-title":"Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells","volume":"56","author":"Seufferlein","year":"1996","journal-title":"Cancer Res"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1006\/bbrc.1998.9118","article-title":"Osteoblastic differentiation is enhanced by rapamycin in rat osteoblast-like osteosarcoma (ROS 17\/2.8) cells","volume":"249","author":"Ogawa","year":"1998","journal-title":"Biochem. Biophys. Res. Commun"},{"key":"ref_181","first-page":"3581","article-title":"Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells","volume":"59","author":"Grewe","year":"1999","journal-title":"Cancer Res"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1023\/A:1012570204923","article-title":"Estrogen and rapamycin effects on cell cycle progression in T47D breast cancer cells","volume":"70","author":"Pang","year":"2001","journal-title":"Breast Cancer Res. Treat"},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s00240-002-0282-1","article-title":"Rapamycin induces Smad activity in prostate cancer cell lines","volume":"30","author":"Hanrahan","year":"2003","journal-title":"Urol. Res"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1097\/00007890-199508000-00010","article-title":"Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells","volume":"60","author":"Muthukkumar","year":"1995","journal-title":"Transplantation"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ccr.2006.07.003","article-title":"Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin","volume":"10","author":"Phung","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nm1337","article-title":"Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer","volume":"12","author":"Thomas","year":"2006","journal-title":"Nat. Med"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.1101\/gad.912401","article-title":"Hierarchical phosphorylation of the translation inhibitor 4E-BP1","volume":"15","author":"Gingras","year":"2001","journal-title":"Genes Dev"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0024-3205(95)02233-3","article-title":"Mechanism of action of the immunosuppressant rapamycin","volume":"58","author":"Dumont","year":"1996","journal-title":"Life Sci"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.4161\/cbt.5.9.3175","article-title":"Therapeutic targets: MTOR and related pathways","volume":"5","author":"Dancey","year":"2006","journal-title":"Cancer Biol. Ther"},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1158\/1078-0432.CCR-07-4719","article-title":"Temsirolimus, an inhibitor of mammalian target of rapamycin","volume":"14","author":"Rini","year":"2008","journal-title":"Clin. Cancer Res"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2756","DOI":"10.1158\/1078-0432.CCR-07-1372","article-title":"A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies","volume":"14","author":"Rizzieri","year":"2008","journal-title":"Clin. Cancer Res"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1200\/JCO.2008.18.9514","article-title":"Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer","volume":"27","author":"Wolpin","year":"2009","journal-title":"J. Clin. Oncol"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/ajh.21664","article-title":"A Phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma","volume":"85","author":"Johnston","year":"2010","journal-title":"Am. J. Hematol"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/leu.2010.226","article-title":"A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma","volume":"25","author":"Witzig","year":"2011","journal-title":"Leukemia"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"4536","DOI":"10.1200\/JCO.2008.21.3033","article-title":"Randomized phase II study comparing two schedules of everolimus in patients with recurrent\/metastatic breast cancer: NCIC Clinical Trials Group IND.163","volume":"27","author":"Ellard","year":"2009","journal-title":"J. Clin. Oncol"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"3278","DOI":"10.1200\/JCO.2010.34.1578","article-title":"Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: A trial of the NCIC Clinical Trials Group","volume":"29","author":"Oza","year":"2011","journal-title":"J. Clin. Oncol"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1200\/JCO.2008.20.7977","article-title":"Phase III study to evaluate temsirolimus compared with investigator\u2019s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma","volume":"27","author":"Hess","year":"2009","journal-title":"J. Clin. Oncol"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1158\/0008-5472.CAN-05-2925","article-title":"mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt","volume":"66","author":"Rojo","year":"2006","journal-title":"Cancer Res"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"5549","DOI":"10.1158\/0008-5472.CAN-05-2825","article-title":"Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus","volume":"66","author":"Ciuffreda","year":"2006","journal-title":"Cancer Res"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/nrclinonc.2010.42","article-title":"Alterations in VHL as potential biomarkers in renal-cell carcinoma","volume":"7","author":"Gossage","year":"2010","journal-title":"Nat. Rev. Clin. Oncol"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"e38","DOI":"10.1371\/journal.pbio.1000038","article-title":"Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2","volume":"7","author":"Feldman","year":"2009","journal-title":"PLoS Biol"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"8023","DOI":"10.1074\/jbc.M900301200","article-title":"An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1","volume":"284","author":"Thoreen","year":"2009","journal-title":"J. Biol. Chem"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1756-8722-1-20","article-title":"First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American society of clinical oncology meeting","volume":"1","author":"Molckovsky","year":"2008","journal-title":"J. Hematol. Oncol"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.coph.2008.08.004","article-title":"Targeting the PI3K-AKT-mTOR pathway: Progress, pitfalls, and promises","volume":"8","author":"Yap","year":"2008","journal-title":"Curr. Opin. Pharmacol"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1158\/1535-7163.MCT-09-0160","article-title":"NVP-BEZ235, a novel dual phosphatidylinositol 3-kinase\/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas","volume":"8","author":"Liu","year":"2009","journal-title":"Mol. Cancer Ther"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12154-008-0003-5","article-title":"Rapamycin and mTOR kinase inhibitors","volume":"1","author":"Ballou","year":"2008","journal-title":"J. Chem. Biol"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1158\/0008-5472.CAN-09-1751","article-title":"AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity","volume":"70","author":"Chresta","year":"2010","journal-title":"Cancer Res"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1042\/BJ20090489","article-title":"Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)","volume":"421","author":"Moran","year":"2009","journal-title":"Biochem. J"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"6232","DOI":"10.1158\/0008-5472.CAN-09-0299","article-title":"Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin","volume":"69","author":"Yu","year":"2009","journal-title":"Cancer Res"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"5840","DOI":"10.1158\/0008-5472.CAN-06-4615","article-title":"Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases","volume":"67","author":"Raynaud","year":"2007","journal-title":"Cancer Res"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1016\/j.bmcl.2010.07.104","article-title":"PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)\/mammalian target of rapamycin (mTOR) inhibitor","volume":"20","author":"Venkatesan","year":"2010","journal-title":"Bioorg. Med. Chem. Lett"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1021\/jm901830p","article-title":"Bis(morpholino-1,3,5-triazine) derivatives: Potent adenosine 5\u2032-triphosphate competitive phosphatidylinositol-3-kinase\/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor","volume":"53","author":"Venkatesan","year":"2010","journal-title":"J. Med. Chem"},{"key":"ref_213","first-page":"6141","article-title":"Inhibitors of mTOR reverse doxorubicin resistance conferred by PTEN status in prostate cancer cells","volume":"62","author":"Grunwald","year":"2002","journal-title":"Cancer Res"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"7031","DOI":"10.1158\/1078-0432.CCR-04-0361","article-title":"Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells","volume":"10","author":"Mondesire","year":"2004","journal-title":"Clin. Cancer Res"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"4086","DOI":"10.1038\/onc.2008.49","article-title":"Suppression of PTEN function increases breast cancer chemotherapeutic drug resistance while conferring sensitivity to mTOR inhibitors","volume":"27","author":"Steelman","year":"2008","journal-title":"Oncogene"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s11060-008-9741-z","article-title":"A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM)","volume":"92","author":"Kreisl","year":"2009","journal-title":"J. Neurooncol"},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s11060-009-9950-0","article-title":"Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma","volume":"96","author":"Reardon","year":"2010","journal-title":"J. Neurooncol"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"1979","DOI":"10.1158\/1078-0432.CCR-09-1823","article-title":"New strategies in estrogen receptor-positive breast cancer","volume":"16","author":"Johnston","year":"2010","journal-title":"Clin. Cancer Res"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1200\/JCO.2010.32.2321","article-title":"Phase I\/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy","volume":"29","author":"Morrow","year":"2011","journal-title":"J. Clin. Oncol"},{"key":"ref_220","doi-asserted-by":"crossref","unstructured":"Merchan, J.R., Pitot, H.C., Qin, R., Liu, G., Fitch, T.R., Picus, J., Maples, W.J., and Erlichman, C (2009). Phase I\/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): Safety and activity in RTKI refractory RCC patients. J. Clin. Oncol, 27, abstract 5039.","DOI":"10.1200\/jco.2009.27.15_suppl.5039"},{"key":"ref_221","doi-asserted-by":"crossref","unstructured":"Patnaik, A., Ricart, A., Cooper, J., Papadopoulos, K., Beeram, M., Mita, C., Mita, M.M., Hufnagel, D., Izbicka, E., and Tolcher, A.W. (2007). A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies. J. Clin. Oncol, 25, abstract 3512.","DOI":"10.1200\/jco.2007.25.18_suppl.3512"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3816\/CGC.2009.n.004","article-title":"Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma","volume":"7","author":"Patel","year":"2009","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_223","doi-asserted-by":"crossref","unstructured":"Houghton, P (2008, January 20\u201323). Targeting the IGF-1\/mTOR pathway. Monterey, CA, USA. Abstract number PL05-03.","DOI":"10.1158\/1940-6207.PREV-08-PL05-03"},{"key":"ref_224","unstructured":"Kurmasheva, R.T., Easton, J.B., and Houghton, P.J. (2008). Combined targeting of mTOR and the insulin-like growth factor pathway. ASCO Educ. Book 2008, 460\u2013464."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1038\/jid.2008.44","article-title":"Combined inhibition of MAPK and mTOR signaling inhibits growth, induces cell death, and abrogates invasive growth of melanoma cells","volume":"128","author":"Lasithiotakis","year":"2008","journal-title":"J. Invest. Dermatol"},{"key":"ref_226","doi-asserted-by":"crossref","unstructured":"McDaid, H.M., Legrier, M., Yang, C.H., Yan, H.G., Lopez-Barcons, L., Keller, S.M., and Horwitz, S.B. (2007). Combined MEK and mTOR suppression is synergistic in human NSCLC and is mediated via inhibition of protein translation. J. Clin. Oncol, 25, abstract 10615.","DOI":"10.1200\/jco.2007.25.18_suppl.10615"},{"key":"ref_227","doi-asserted-by":"crossref","unstructured":"Molhoek, K.R., Brautigan, D.L., and Slingluff, C.L. (2005). Synergistic inhibition of human melanoma proliferation by combination treatment with B-Raf inhibitor BAY43-9006 and mTOR inhibitor Rapamycin. J. Transl. Med, 3.","DOI":"10.1186\/1479-5876-3-39"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1016\/j.ejca.2004.08.017","article-title":"Rapamycin inhibits doxorubicin-induced NF-\u03baB\/Rel nuclear activity and enhances the apoptosis of melanoma cells","volume":"40","author":"Romano","year":"2004","journal-title":"Eur. J. Cancer"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1111\/j.1365-2133.2008.08991.x","article-title":"Suppression of mTOR complex 2-dependent AKT phosphorylation in melanoma cells by combined treatment with rapamycin and LY294002","volume":"160","author":"Werzowa","year":"2009","journal-title":"Br. J. Dermatol"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1159\/000101008","article-title":"CCI-779 plus cisplatin is highly effective against human melanoma in a SCID mouse xenotranplantation model","volume":"79","author":"Thallinger","year":"2007","journal-title":"Pharmacology"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.drup.2007.09.001","article-title":"Overcoming apoptosis deficiency of melanoma-hope for new therapeutic approaches","volume":"10","author":"Eberle","year":"2007","journal-title":"Drug Resist. Updat"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1158\/1078-0432.CCR-03-0043","article-title":"Determinants of rapamycin sensitivity in breast cancer cells","volume":"10","author":"Noh","year":"2004","journal-title":"Clin. Cancer Res"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"10314","DOI":"10.1073\/pnas.171076798","article-title":"Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP\/mTOR","volume":"98","author":"Neshat","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1677\/erc.0.0080249","article-title":"mTOR, a novel target in breast cancer: The effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer","volume":"8","author":"Yu","year":"2001","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_235","doi-asserted-by":"crossref","unstructured":"Cloughesy, T.F., Yoshimoto, K., Nghiemphu, P., Brown, K., Dang, J., Zhu, S., Hsueh, T., Chen, Y., Wang, W., and Youngkin, D. (2008). Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. 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