{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:21:36Z","timestamp":1790760096738,"version":"4.1.0"},"reference-count":206,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2018,1,19]],"date-time":"2018-01-19T00:00:00Z","timestamp":1516320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy.<\/jats:p>","DOI":"10.3390\/cancers10010023","type":"journal-article","created":{"date-parts":[[2018,1,22]],"date-time":"2018-01-22T04:51:13Z","timestamp":1516596673000},"page":"23","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":127,"title":["mTOR Cross-Talk in Cancer and Potential for Combination Therapy"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8579-5222","authenticated-orcid":false,"given":"Fabiana","family":"Conciatori","sequence":"first","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"},{"name":"Department of Medical-surgical Sciences and Translational Medicine, University of Rome, La Sapienza, Rome 00185, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7964-7119","authenticated-orcid":false,"given":"Ludovica","family":"Ciuffreda","sequence":"additional","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1648-3700","authenticated-orcid":false,"given":"Chiara","family":"Bazzichetto","sequence":"additional","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"},{"name":"Department of Molecular Medicine, University of Rome, La Sapienza, Rome 00185, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Italia","family":"Falcone","sequence":"additional","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pilotto","sequence":"additional","affiliation":[{"name":"Medical OncologyUnit, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona 37100, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Bria","sequence":"additional","affiliation":[{"name":"Medical OncologyUnit, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona 37100, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8579-5222","authenticated-orcid":false,"given":"Francesco","family":"Cognetti","sequence":"additional","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Milella","sequence":"additional","affiliation":[{"name":"Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome 00144, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR signaling in growth, metabolism, and disease","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"497","DOI":"10.2967\/jnumed.111.089623","article-title":"mTOR signaling, function, novel inhibitors, and therapeutic targets","volume":"52","author":"Watanabe","year":"2011","journal-title":"J. Nucl. Med."},{"key":"ref_4","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_5","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_6","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_7","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_8","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_9","doi-asserted-by":"crossref","first-page":"20036","DOI":"10.1074\/jbc.M702376200","article-title":"PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding","volume":"282","author":"Wang","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.molcel.2011.03.017","article-title":"Rac1 regulates the activity of mTORC1 and mTORC2 and controls cellular size","volume":"42","author":"Saci","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1128\/MCB.00824-10","article-title":"Regulation of mTORC1 complex assembly and signaling by GRp58\/ERp57","volume":"31","year":"2011","journal-title":"Mol. Cell Biol."},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"2305","DOI":"10.4161\/cc.10.14.16586","article-title":"mTOR complex 2 signaling and functions","volume":"10","author":"Oh","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_14","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_15","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_16","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_17","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1111\/bph.12749","article-title":"Therapeutic targeting of the mTOR-signalling pathway in cancer: Benefits and limitations","volume":"171","author":"Moschetta","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11818","DOI":"10.1073\/pnas.1716173114","article-title":"Twenty-five years of mTOR: Uncovering the link from nutrients to growth","volume":"114","author":"Sabatini","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D945","DOI":"10.1093\/nar\/gkq929","article-title":"Cosmic: Mining complete cancer genomes in the catalogue of somatic mutations in cancer","volume":"39","author":"Forbes","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Xie, J., Wang, X., and Proud, C.G. (2016). mTOR inhibitors in cancer therapy. F1000Res., 5.","DOI":"10.12688\/f1000research.9207.1"},{"key":"ref_21","first-page":"e28174","article-title":"Signaling crosstalk between the mTOR complexes","volume":"2","author":"Xie","year":"2014","journal-title":"Translation (Austin)"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1453","DOI":"10.1152\/ajpendo.00660.2011","article-title":"Role of PRAS40 in Akt and mTOR signaling in health and disease","volume":"302","author":"Wiza","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_23","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_24","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_25","doi-asserted-by":"crossref","first-page":"20109","DOI":"10.1074\/jbc.M110.121699","article-title":"Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly","volume":"285","author":"Kaizuka","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"25604","DOI":"10.1074\/jbc.M704343200","article-title":"PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor \u03b2 expression and signaling","volume":"282","author":"Woo","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.molcel.2011.08.030","article-title":"mTOR drives its own activation via SCF\u03b2TrCP-dependent degradation of the mTOR inhibitor DEPTOR","volume":"44","author":"Gao","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_29","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_30","doi-asserted-by":"crossref","unstructured":"Kakumoto, K., Ikeda, J., Okada, M., Morii, E., and Oneyama, C. (2015). mLST8 promotes mTOR-mediated tumor progression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119015"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1083\/jcb.144.6.1235","article-title":"Rho GTPases control polarity, protrusion, and adhesion during cell movement","volume":"144","author":"Nobes","year":"1999","journal-title":"J. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.semcdb.2014.08.004","article-title":"mTORC1 signaling controls multiple steps in ribosome biogenesis","volume":"36","author":"Iadevaia","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ceb.2017.02.012","article-title":"mTORC1 signaling and the metabolic control of cell growth","volume":"45","author":"Manning","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_34","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_35","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1042\/BJ20081668","article-title":"mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1)","volume":"416","author":"Alessi","year":"2008","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrm2672","article-title":"Molecular mechanisms of mTOR-mediated translational control","volume":"10","author":"Ma","year":"2009","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_37","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_38","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1126\/science.1187532","article-title":"mTORC1-mediated cell proliferation, but not cell growth, controlled by the 4E-BPS","volume":"328","author":"Dowling","year":"2010","journal-title":"Science"},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1101\/gad.12.4.502","article-title":"4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway","volume":"12","author":"Gingras","year":"1998","journal-title":"Genes Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.cell.2005.10.024","article-title":"mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events","volume":"123","author":"Holz","year":"2005","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1128\/MCB.24.7.2986-2997.2004","article-title":"A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin","volume":"24","author":"Browne","year":"2004","journal-title":"Mol. Cell Biol."},{"key":"ref_43","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_44","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_45","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_46","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_47","doi-asserted-by":"crossref","first-page":"7004","DOI":"10.1128\/MCB.22.20.7004-7014.2002","article-title":"Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin","volume":"22","author":"Hudson","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_48","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_49","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_50","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1158\/2159-8290.CD-15-0460","article-title":"Ptdins(3,4,5)P3-dependent activation of the mTORC2 kinase complex","volume":"5","author":"Liu","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/ncb2507","article-title":"PRR5L degradation promotes mTORC2-mediated PKC-\u03b4 phosphorylation and cell migration downstream of G\u03b112","volume":"14","author":"Gan","year":"2012","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1083\/jcb.201205030","article-title":"Ablation of the mTORC2 component rictor in brain or purkinje cells affects size and neuron morphology","volume":"201","author":"Thomanetz","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1073\/pnas.1314469111","article-title":"mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy","volume":"111","author":"Weiler","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.molcel.2007.10.035","article-title":"FOXO3A is activated in response to hypoxic stress and inhibits HIF1-induced apoptosis via regulation of CITED2","volume":"28","author":"Bakker","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1172\/JCI28984","article-title":"PDGFRS are critical for PI3K\/Akt activation and negatively regulated by mTOR","volume":"117","author":"Zhang","year":"2007","journal-title":"J. Clin. Invest."},{"key":"ref_56","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_57","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/ncb840","article-title":"Akt regulates growth by directly phosphorylating Tsc2","volume":"4","author":"Potter","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13489","DOI":"10.1073\/pnas.0405659101","article-title":"Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase","volume":"101","author":"Roux","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_59","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_60","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.molcel.2012.06.009","article-title":"TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1","volume":"47","author":"Dibble","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"52","DOI":"10.12703\/P6-52","article-title":"mTOR and lysosome regulation","volume":"6","author":"Puertollano","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"8204","DOI":"10.1073\/pnas.0502857102","article-title":"The coordinate regulation of the p53 and mTOR pathways in cells","volume":"102","author":"Feng","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","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_64","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nrc2501","article-title":"Hypoxia signalling through mTOR and the unfolded protein response in cancer","volume":"8","author":"Wouters","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_65","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_66","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Sancak","year":"2008","journal-title":"Science"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2010.02.024","article-title":"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids","volume":"141","author":"Sancak","year":"2010","journal-title":"Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.1232044","article-title":"A tumor suppressor complex with gap activity for the Rag GTPases that signal amino acid sufficiency to mTORC1","volume":"340","author":"Chantranupong","year":"2013","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s11912-012-0227-y","article-title":"PI3K and mTOR signaling pathways in cancer: New data on targeted therapies","volume":"14","author":"Willems","year":"2012","journal-title":"Curr. Oncol. Rep."},{"key":"ref_70","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_71","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1126\/science.1199498","article-title":"The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling","volume":"332","author":"Hsu","year":"2011","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1126\/science.1199484","article-title":"Phosphoproteomic analysis identifies GRB10 as an mTORC1 substrate that negatively regulates insulin signaling","volume":"332","author":"Yu","year":"2011","journal-title":"Science"},{"key":"ref_73","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_74","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev-med-062913-051343","article-title":"The PI3K\/Akt pathway as a target for cancer treatment","volume":"67","author":"Mayer","year":"2016","journal-title":"Annu. Rev. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"19382","DOI":"10.1074\/jbc.M200732200","article-title":"ERK negatively regulates the epidermal growth factor-mediated interaction of GAB1 and the phosphatidylinositol 3-kinase","volume":"277","author":"Yu","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1741","DOI":"10.1126\/science.286.5445.1741","article-title":"Phosphorylation and regulation of Raf by Akt (protein kinase b)","volume":"286","author":"Zimmermann","year":"1999","journal-title":"Science"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00109-011-0844-1","article-title":"The mitogen-activated protein kinase (MAPK) cascade controls phosphatase and tensin homolog (PTEN) expression through multiple mechanisms","volume":"90","author":"Ciuffreda","year":"2012","journal-title":"J. Mol. Med. (Berl.)"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"43013","DOI":"10.1038\/srep43013","article-title":"PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer","volume":"7","author":"Milella","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2896","DOI":"10.1093\/annonc\/mdx335","article-title":"Lack of growth inhibitory synergism with combined MAPK\/PI3K inhibition in preclinical models of pancreatic cancer","volume":"28","author":"Ciuffreda","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/cas.13169","article-title":"Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus","volume":"108","author":"Matsuki","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Wang, C., Gao, D., Guo, K., Kang, X., Jiang, K., Sun, C., Li, Y., Sun, L., Shu, H., and Jin, G. (2012). Novel synergistic antitumor effects of rapamycin with bortezomib on hepatocellular carcinoma cells and orthotopic tumor model. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-166"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1038\/leu.2008.158","article-title":"The dual PI3 kinase\/mTOR inhibitor PI-103 prevents p53 induction by MDM2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML","volume":"22","author":"Kojima","year":"2008","journal-title":"Leukemia"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.molonc.2013.11.007","article-title":"TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms","volume":"8","author":"Simmons","year":"2014","journal-title":"Mol. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"83","DOI":"10.21873\/cgp.20021","article-title":"Combination of a STAT3 inhibitor and an mTOR inhibitor against a temozolomide-resistant glioblastoma cell line","volume":"14","author":"Miyata","year":"2017","journal-title":"Cancer Genomics Proteomics"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/S0960-9822(00)00177-9","article-title":"The activation of phosphatidylinositol 3-kinase by Ras","volume":"4","author":"Kodaki","year":"1994","journal-title":"Curr. Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20080281","article-title":"The TSC1-TSC2 complex: A molecular switchboard controlling cell growth","volume":"412","author":"Huang","year":"2008","journal-title":"Biochem. J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.cub.2008.07.078","article-title":"Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation","volume":"18","author":"Carriere","year":"2008","journal-title":"Curr. Biol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrc.2017.51","article-title":"Microenvironmental regulation of tumour angiogenesis","volume":"17","author":"Biziato","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","article-title":"Activation of a metabolic gene regulatory network downstream of mTOR complex 1","volume":"39","author":"Duvel","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_90","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_91","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1101\/gad.1617608","article-title":"Hypoxia regulates TSC1\/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling","volume":"22","author":"DeYoung","year":"2008","journal-title":"Genes Dev."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1158\/2326-6066.CIR-14-0112","article-title":"NF-\u03baB, an active player in human cancers","volume":"2","author":"Xia","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"18934","DOI":"10.1074\/jbc.M101103200","article-title":"Akt stimulates the transactivation potential of the RELA\/P65 subunit of NF-\u03baB through utilization of the I\u03baB kinase and activation of the mitogen-activated protein kinase P38","volume":"276","author":"Madrid","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6263","DOI":"10.1158\/0008-5472.CAN-07-1232","article-title":"Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I\u03baB kinase \u03b1","volume":"67","author":"Dan","year":"2007","journal-title":"Cancer Res."},{"key":"ref_95","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_96","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev.pharmtox.46.120604.141300","article-title":"The proteasome and proteasome inhibitors in cancer therapy","volume":"46","author":"Voorhees","year":"2006","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"O\u2019Sullivan, G., Leleu, X., Jia, X., Hatjiharisi, E., Ngo, H., Moreau, A.S., Tai, Y.T., McMillin, D., Mitsiades, C., and Raje, N. (2006). The combination of the mTOR inhibitor rapamycin and proteasome inhibitor bortezomib is synergistic in vitro in multiple myeloma. The American Society of Hematology, Blood.","DOI":"10.1182\/blood.V108.11.3495.3495"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9660","DOI":"10.1073\/pnas.1002298107","article-title":"Paradoxical suppression of cellular senescence by p53","volume":"107","author":"Demidenko","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","first-page":"344","article-title":"The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway","volume":"2","author":"Korotchkina","year":"2010","journal-title":"Aging (Albany N. Y.)"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S1097-2765(01)00323-9","article-title":"Regulation of PTEN transcription by p53","volume":"8","author":"Stambolic","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"11598","DOI":"10.1073\/pnas.181181198","article-title":"A phosphatidylinositol 3-kinase\/Akt pathway promotes translocation of MDM2 from the cytoplasm to the nucleus","volume":"98","author":"Mayo","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.4161\/15384047.2014.955743","article-title":"mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels","volume":"15","author":"Goudarzi","year":"2014","journal-title":"Cancer Biol. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Shimazu, K., Tada, Y., Morinaga, T., Shingyoji, M., Sekine, I., Shimada, H., Hiroshima, K., Namiki, T., Tatsumi, K., and Tagawa, M. (2017). Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3300-y"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"4423","DOI":"10.1038\/onc.2015.513","article-title":"Epigenomic regulation of oncogenesis by chromatin remodeling","volume":"35","author":"Kumar","year":"2016","journal-title":"Oncogene"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/nrd.2016.256","article-title":"Marked for death: Targeting epigenetic changes in cancer","volume":"16","author":"Pfister","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1158\/1535-7163.MCT-17-0171","article-title":"Cooperative targets of combined mTOR\/HDAC inhibition promote MYC degradation","volume":"16","author":"Simmons","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"52269","DOI":"10.18632\/oncotarget.13699","article-title":"The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed\/refractory acute myeloid leukemia: A phase Ib\/II study","volume":"8","author":"Tan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1046\/j.1523-1755.2001.00460.x","article-title":"Rapamycin in transplantation: A review of the evidence","volume":"59","author":"Saunders","year":"2001","journal-title":"Kidney Int."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.it.2014.10.006","article-title":"Intersection of mtor and STAT signaling in immunity","volume":"36","author":"Saleiro","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.immuni.2009.10.010","article-title":"The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin","volume":"32","author":"Rao","year":"2010","journal-title":"Immunity"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.immuni.2011.04.006","article-title":"A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity","volume":"34","author":"Li","year":"2011","journal-title":"Immunity"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nri2093","article-title":"SOCS proteins, cytokine signalling and immune regulation","volume":"7","author":"Yoshimura","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1182\/blood-2008-02-137430","article-title":"Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells","volume":"112","author":"Ohtani","year":"2008","journal-title":"Blood"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3919","DOI":"10.4049\/jimmunol.1000296","article-title":"A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation","volume":"185","author":"Haidinger","year":"2010","journal-title":"J. Immunol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"5217","DOI":"10.4049\/jimmunol.1002513","article-title":"Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-\u03b2-signaling pathways regulates the innate inflammatory response","volume":"186","author":"Wang","year":"2011","journal-title":"J. Immunol."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Bogani, C., Bartalucci, N., Martinelli, S., Tozzi, L., Guglielmelli, P., Bosi, A., and Vannucchi, A.M. (2013). Associazione Italiana per la Ricerca sul Cancro AGIMM Gruppo Italiano Malattie Mieloproliferative. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054826"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"484","DOI":"10.2174\/156800910791517172","article-title":"The mTOR pathway: A new target in cancer therapy","volume":"10","author":"Ciuffreda","year":"2010","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_118","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_119","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1158\/2159-8290.CD-13-0929","article-title":"A diverse array of cancer-associated mTOR mutations are hyperactivating and can predict rapamycin sensitivity","volume":"4","author":"Grabiner","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1158\/2159-8290.CD-14-0971","article-title":"Rictor amplification defines a novel subset of patients with lung cancer who may benefit from treatment with mTORC1\/2 inhibitors","volume":"5","author":"Cheng","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"4752","DOI":"10.1158\/0008-5472.CAN-15-3393","article-title":"Rictor\/mTORC2 drives progression and therapeutic resistance of HER2-amplified breast cancers","volume":"76","author":"Hicks","year":"2016","journal-title":"Cancer Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1158\/2159-8290.CD-13-0286","article-title":"Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets","volume":"4","author":"Balko","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"S266","DOI":"10.1016\/j.jtho.2016.11.260","article-title":"Druggable alterations involving crucial carcinogenesis pathways drive the prognosis of squamous cell lung carcinoma (SQCLC)","volume":"12","author":"Pilotto","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrd2926","article-title":"Targeting the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"Liu","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ccr.2008.12.017","article-title":"mTOR complex 2 is required for the development of prostate cancer induced by PTEN loss in mice","volume":"15","author":"Guertin","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fonc.2015.00024","article-title":"PTEN: Multiple functions in human malignant tumors","volume":"5","author":"Milella","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_127","first-page":"5027","article-title":"Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779","volume":"62","author":"Shi","year":"2002","journal-title":"Cancer Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1093\/annonc\/mdh388","article-title":"Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase\/Akt pathway","volume":"15","author":"DeGraffenried","year":"2004","journal-title":"Ann. Oncol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"247.e1","DOI":"10.1016\/j.ajog.2006.10.872","article-title":"Reduced progression of endometrial hyperplasia with oral mTOR inhibition in the PTEN heterozygote murine model","volume":"196","author":"Milam","year":"2007","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"17022","DOI":"10.1038\/celldisc.2017.22","article-title":"Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities","volume":"3","author":"Pulito","year":"2017","journal-title":"Cell Discov."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrm3025","article-title":"mTOR: From growth signal integration to cancer, diabetes and ageing","volume":"12","author":"Zoncu","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1101\/gad.1199104","article-title":"Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and peutz-jeghers syndrome","volume":"18","author":"Corradetti","year":"2004","journal-title":"Genes Dev."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1126\/science.1228792","article-title":"Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1","volume":"339","author":"Howell","year":"2013","journal-title":"Science"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1126\/science.aad0489","article-title":"mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle","volume":"351","author":"Hoxhaj","year":"2016","journal-title":"Science"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1200\/JCO.2007.11.0395","article-title":"Targeting human epidermal growth factor receptor 2: It is time to kill kinase death human epidermal growth factor receptor 3","volume":"25","author":"Menendez","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"3892","DOI":"10.1158\/0008-5472.CAN-03-2904","article-title":"Akt stimulates aerobic glycolysis in cancer cells","volume":"64","author":"Elstrom","year":"2004","journal-title":"Cancer Res."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ccr.2007.07.006","article-title":"HIF and C-MYC: Sibling rivals for control of cancer cell metabolism and proliferation","volume":"12","author":"Gordan","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"12297","DOI":"10.1074\/jbc.M900573200","article-title":"ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy","volume":"284","author":"Ganley","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1091\/mbc.e08-12-1248","article-title":"Nutrient-dependent mTORC1 association with the ULK1-ATG13-FIP200 complex required for autophagy","volume":"20","author":"Hosokawa","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1091\/mbc.e08-12-1249","article-title":"ULK-ATG13-FIP200 complexes mediate mTOR signaling to the autophagy machinery","volume":"20","author":"Jung","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrm3565","article-title":"Signals from the lysosome: A control centre for cellular clearance and energy metabolism","volume":"14","author":"Settembre","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1038\/nature12865","article-title":"P53 status determines the role of autophagy in pancreatic tumour development","volume":"504","author":"Rosenfeldt","year":"2013","journal-title":"Nature"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1056\/NEJMcibr1400189","article-title":"Autophagy, p53, and pancreatic cancer","volume":"370","author":"Herman","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/bcp.12844","article-title":"Therapeutic potential of mTOR inhibitors for targeting cancer stem cells","volume":"82","author":"Francipane","year":"2016","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1182\/blood-2009-06-229443","article-title":"Constitutively active Akt depletes hematopoietic stem cells and induces leukemia in mice","volume":"115","author":"Kharas","year":"2010","journal-title":"Blood"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature04747","article-title":"PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention","volume":"441","author":"Zhang","year":"2006","journal-title":"Nature"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jbior.2014.07.002","article-title":"PTEN expression and function in adult cancer stem cells and prospects for therapeutic targeting","volume":"56","author":"Ciuffreda","year":"2014","journal-title":"Adv. Biol. Regul."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nature04703","article-title":"PTEN dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells","volume":"441","author":"Yilmaz","year":"2006","journal-title":"Nature"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1084\/jem.20081297","article-title":"TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species","volume":"205","author":"Chen","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.stem.2009.06.017","article-title":"mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging","volume":"5","author":"Castilho","year":"2009","journal-title":"Cell Stem Cell"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/nature11163","article-title":"mTORC1 in the paneth cell niche couples intestinal stem-cell function to calorie intake","volume":"486","author":"Yilmaz","year":"2012","journal-title":"Nature"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1038\/onc.2016.363","article-title":"mTORC1 and mTORC2 in cancer and the tumor microenvironment","volume":"36","author":"Kim","year":"2017","journal-title":"Oncogene"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"38362","DOI":"10.1074\/jbc.M110.141168","article-title":"Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity","volume":"285","author":"Liu","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1158\/0008-5472.CAN-10-4058","article-title":"mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways","volume":"71","author":"Gulhati","year":"2011","journal-title":"Cancer Res."},{"key":"ref_155","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_156","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_157","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_158","doi-asserted-by":"crossref","first-page":"6107","DOI":"10.1158\/0008-5472.CAN-09-0975","article-title":"Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors","volume":"69","author":"Huang","year":"2009","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.1215135","article-title":"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity","volume":"335","author":"Lamming","year":"2012","journal-title":"Science"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1056\/NEJMoa066838","article-title":"Temsirolimus, interferon \u03b1, or both for advanced renal-cell carcinoma","volume":"356","author":"Hudes","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0140-6736(08)61039-9","article-title":"Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial","volume":"372","author":"Motzer","year":"2008","journal-title":"Lancet"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1200\/JCO.2013.50.3961","article-title":"Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma","volume":"32","author":"Hutson","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1056\/NEJMoa1009290","article-title":"Everolimus for advanced pancreatic neuroendocrine tumors","volume":"364","author":"Yao","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/S0140-6736(15)00817-X","article-title":"Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (radiant-4): A randomised, placebo-controlled, phase 3 study","volume":"387","author":"Yao","year":"2016","journal-title":"Lancet"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1200\/JCO.2012.45.5766","article-title":"Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy","volume":"31","author":"Demetri","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_166","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_167","doi-asserted-by":"crossref","first-page":"3935","DOI":"10.1200\/JCO.2012.48.3552","article-title":"Everolimus for previously treated advanced gastric cancer: Results of the randomized, double-blind, phase III granite-1 study","volume":"31","author":"Ohtsu","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1200\/JCO.2013.50.5305","article-title":"Randomized phase III trial of temsirolimus and bevacizumab versus interferon \u03b1 and bevacizumab in metastatic renal cell carcinoma: Intoract trial","volume":"32","author":"Rini","year":"2014","journal-title":"J. Clin. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1016\/S0140-6736(11)61742-X","article-title":"Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (radiant-2): A randomised, placebo-controlled, phase 3 study","volume":"378","author":"Pavel","year":"2011","journal-title":"Lancet"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1056\/NEJMoa1109653","article-title":"Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer","volume":"366","author":"Baselga","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/S1470-2045(14)70138-X","article-title":"Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial","volume":"15","author":"Andre","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1200\/JCO.2011.38.3331","article-title":"Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer","volume":"31","author":"Wolff","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/S1470-2045(15)00290-9","article-title":"Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: A randomised, phase 2, open-label, multicentre trial","volume":"16","author":"Motzer","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.hoc.2012.02.014","article-title":"mTOR signaling pathway and mTOR inhibitors in cancer therapy","volume":"26","author":"Ferrari","year":"2012","journal-title":"Hematol. Oncol. Clin. North Am."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.tips.2014.11.004","article-title":"Current treatment strategies for inhibiting mTOR in cancer","volume":"36","author":"Chiarini","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1158\/1078-0432.CCR-14-3239","article-title":"Molecular pathways: Increased susceptibility to infection is a complication of mTOR inhibitor use in cancer therapy","volume":"22","author":"Eiden","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1007\/s00520-013-1826-3","article-title":"Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: Observations from a phase III clinical trial","volume":"21","author":"Peterson","year":"2013","journal-title":"Support. Care Cancer"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.ctrv.2013.08.004","article-title":"Noninfectious pneumonitis with the use of mTOR inhibitors in breast cancer","volume":"40","author":"Peddi","year":"2014","journal-title":"Cancer Treat Rev."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cmet.2014.01.001","article-title":"Rapamycin: One drug, many effects","volume":"19","author":"Li","year":"2014","journal-title":"Cell Metab."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"7181","DOI":"10.18632\/oncotarget.12742","article-title":"Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents","volume":"8","author":"Liu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.coph.2015.05.016","article-title":"Drugging PI3K in cancer: Refining targets and therapeutic strategies","volume":"23","author":"Yap","year":"2015","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ctrv.2017.07.005","article-title":"Phosphoinositide 3-kinase (PI3K) pathway inhibitors in solid tumors: From laboratory to patients","volume":"59","author":"Janku","year":"2017","journal-title":"Cancer Treat Rev."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1517\/13543784.2010.499121","article-title":"New inhibitors of the mammalian target of rapamycin signaling pathway for cancer","volume":"19","author":"Albert","year":"2010","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nature17963","article-title":"Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor","volume":"534","author":"Okaniwa","year":"2016","journal-title":"Nature"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1056\/NEJMoa1403352","article-title":"Response and acquired resistance to everolimus in anaplastic thyroid cancer","volume":"371","author":"Wagle","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.ccell.2017.01.014","article-title":"A kinase inhibitor targeted to mTORC1 drives regression in glioblastoma","volume":"31","author":"Fan","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"1236566","DOI":"10.1126\/science.1236566","article-title":"mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin","volume":"341","author":"Kang","year":"2013","journal-title":"Science"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1158\/1078-0432.CCR-11-2123","article-title":"PIK3CA\/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors","volume":"18","author":"Akcakanat","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"623","DOI":"10.3892\/or.2013.2512","article-title":"A detailed immunohistochemical analysis of the PI3K\/Akt\/mTOR pathway in lung cancer: Correlation with PIK3CA, Akt1, K-Ras or PTEN mutational status and clinicopathological features","volume":"30","author":"Trigka","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1365-2559.2012.04236.x","article-title":"Phosphorylated 4E-binding protein 1 (P-4E-BP1): A novel prognostic marker in human astrocytomas","volume":"61","author":"Korkolopoulou","year":"2012","journal-title":"Histopathology"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"10547","DOI":"10.18632\/oncotarget.7234","article-title":"Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus","volume":"7","author":"Lim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"55582","DOI":"10.18632\/oncotarget.16029","article-title":"Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study","volume":"8","author":"Weeber","year":"2017","journal-title":"Oncotarget"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.eururo.2016.10.007","article-title":"Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma","volume":"71","author":"Hsieh","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_194","doi-asserted-by":"crossref","unstructured":"Parachoniak, C.A., Rankin, A., Gaffney, B., Hartmaier, R., Spritz, D., Erlich, R.L., Miller, V.A., Morosini, D., Stephens, P., and Ross, J.S. (2017). Exceptional durable response to everolimus in a patient with biphenotypic breast cancer harboring an STK11 variant. Cold Spring Harb. Mol. Case Stud., 3.","DOI":"10.1101\/mcs.a000778"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1200\/JCO.2015.63.9161","article-title":"Molecular alterations and everolimus efficacy in human epidermal growth factor receptor 2-overexpressing metastatic breast cancers: Combined exploratory biomarker analysis from BOLERO-1 and BOLERO-3","volume":"34","author":"Andre","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1126\/science.1226344","article-title":"Genome sequencing identifies a basis for everolimus sensitivity","volume":"338","author":"Iyer","year":"2012","journal-title":"Science"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1158\/1535-7163.MCT-14-0768","article-title":"Loss of tuberous sclerosis complex 2 (TSC2) is frequent in hepatocellular carcinoma and predicts response to mtorc1 inhibitor everolimus","volume":"14","author":"Huynh","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1158\/1078-0432.CCR-13-2345","article-title":"Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy","volume":"20","author":"Voss","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/iub.1579","article-title":"Tuberous sclerosis complex: From molecular biology to novel therapeutic approaches","volume":"68","author":"Switon","year":"2016","journal-title":"IUBMB Life"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1186\/s13023-015-0317-7","article-title":"Rapamycin and its analogues (rapalogs) for tuberous sclerosis complex-associated tumors: A systematic review on non-randomized studies using meta-analysis","volume":"10","author":"Sasongko","year":"2015","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.trecan.2016.10.006","article-title":"mTOR signaling confers resistance to targeted cancer drugs","volume":"2","author":"Guri","year":"2016","journal-title":"Trends Cancer"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1093\/annonc\/mdu482","article-title":"A phase Ib trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors","volume":"26","author":"Tolcher","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1001\/jamaoncol.2016.5383","article-title":"Effect of selumetinib and MK-2206 vs oxaliplatin and fluorouracil in patients with metastatic pancreatic cancer after prior therapy: SWOG S1115 study randomized clinical trial","volume":"3","author":"Chung","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1097\/01.ju.0000074870.54671.98","article-title":"Overproduction of vascular endothelial growth factor related to von hippel-lindau tumor suppressor gene mutations and hypoxia-inducible factor-1 \u03b1 expression in renal cell carcinomas","volume":"170","author":"Na","year":"2003","journal-title":"J. Urol."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.clgc.2014.12.011","article-title":"A single-arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell carcinoma","volume":"13","author":"Kanesvaran","year":"2015","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1002\/cncr.26429","article-title":"Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma","volume":"118","author":"Molina","year":"2012","journal-title":"Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/1\/23\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:51:50Z","timestamp":1760194310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/10\/1\/23"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,19]]},"references-count":206,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1]]}},"alternative-id":["cancers10010023"],"URL":"https:\/\/doi.org\/10.3390\/cancers10010023","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,19]]}}}