{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:31:10Z","timestamp":1791361870559,"version":"4.3.1"},"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2013,11,14]],"date-time":"2013-11-14T00:00:00Z","timestamp":1384387200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0080070","type":"journal-article","created":{"date-parts":[[2013,11,14]],"date-time":"2013-11-14T22:41:58Z","timestamp":1384468918000},"page":"e80070","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":55,"title":["Differential Effects of Selective Inhibitors Targeting the PI3K\/AKT\/mTOR Pathway in Acute Lymphoblastic Leukemia"],"prefix":"10.1371","volume":"8","author":[{"given":"Susanne","family":"Badura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Tesanovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Pfeifer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia","family":"Wystub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart A.","family":"Nijmeijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Liebermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. H. Frederik","family":"Falkenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Ruthardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver G.","family":"Ottmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2013,11,14]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/S0165-6147(03)00163-9","article-title":"Phosphoinositide 3-kinase signalling--which way to target?","volume":"24","author":"MP Wymann","year":"2003","journal-title":"Trends Pharmacol Sci"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nrd2926","article-title":"Targeting the phosphoinositide 3-kinase pathway in cancer","volume":"8","author":"P Liu","year":"2009","journal-title":"Nat Rev Drug Discov"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1158\/0008-5472.CAN-04-3888","article-title":"ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors","volume":"65","author":"MG Kharas","year":"2005","journal-title":"Cancer Res"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/sj.leu.2404245","article-title":"Phosphoinositide 3-kinase\/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia","volume":"20","author":"AM Martelli","year":"2006","journal-title":"Leukemia"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1172\/JCI34616","article-title":"PTEN posttranslational inactivation and hyperactivation of the PI3K\/Akt pathway sustain primary T cell leukemia viability","volume":"118","author":"A Silva","year":"2008","journal-title":"J Clin Invest"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1093\/emboj\/16.20.6151","article-title":"Transformation of hematopoietic cells by BCR\/ABL requires activation of a PI-3k\/Akt-dependent pathway","volume":"16","author":"T Skorski","year":"1997","journal-title":"EMBO J"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1038\/sj.leu.2402874","article-title":"Constitutive phosphorylation of Akt\/PKB protein in acute myeloid leukemia: its significance as a prognostic variable","volume":"17","author":"YH Min","year":"2003","journal-title":"Leukemia"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1182\/asheducation-2005.1.118","article-title":"Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia","author":"OG Ottmann","year":"2005","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"3995","DOI":"10.1182\/blood.V91.11.3995","article-title":"Clinical significance of cytogenetic abnormalities in adult acute lymphoblastic leukemia","volume":"91","author":"S Faderl","year":"1998","journal-title":"Blood"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1182\/asheducation-2009.1.371","article-title":"Management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL)","author":"OG Ottmann","year":"2009","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1080\/10428190310001625755","article-title":"Mechanisms of resistance to STI571 (Imatinib) in Philadelphia-chromosome positive acute lymphoblastic leukemia","volume":"45","author":"WK Hofmann","year":"2004","journal-title":"Leuk Lymphoma"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1182\/blood-2010-12-326405","article-title":"BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet","volume":"118","author":"S Soverini","year":"2011","journal-title":"Blood"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1172\/JCI33337","article-title":"Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K\/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells","volume":"118","author":"MG Kharas","year":"2008","journal-title":"J Clin Invest"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1038\/sj.leu.2403898","article-title":"Compensatory PI3-kinase\/Akt\/mTor activation regulates imatinib resistance development","volume":"19","author":"A Burchert","year":"2005","journal-title":"Leukemia"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1756-8722-4-6","article-title":"BCR-ABL1-independent PI3Kinase activation causing imatinib-resistance","volume":"4","author":"H Quentmeier","year":"2011","journal-title":"Hematol Oncol"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.leukres.2011.12.018","article-title":"The study of resistant mechanisms and reversal in an imatinib resistant Ph+ acute lymphoblastic leukemia cell line","volume":"36","author":"H Xing","year":"2012","journal-title":"Leuk Res"},{"key":"ref17","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":"DA Guertin","year":"2007","journal-title":"Cancer Cell"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.1038\/onc.2010.139","article-title":"Targeting mTOR: prospects for mTOR complex 2 inhibitors in cancer therapy","volume":"29","author":"CA Sparks","year":"2010","journal-title":"Oncogene"},{"key":"ref19","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":"S Wullschleger","year":"2006","journal-title":"Cell"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrm2672","article-title":"Molecular mechanisms of mTOR-mediated translational control","volume":"10","author":"XM Ma","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref21","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":"K Hara","year":"2002","journal-title":"Cell"},{"key":"ref22","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":"DD Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref23","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":"ME Feldman","year":"2009","journal-title":"PLOS Biol"},{"key":"ref24","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":"CC Thoreen","year":"2009","journal-title":"J Biol Chem"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nm.2091","article-title":"Effective and selective targeting of leukemia cells using a TORC1\/2 kinase inhibitor","volume":"16","author":"MR Janes","year":"2010","journal-title":"Nat Med"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"15113","DOI":"10.1073\/pnas.2436348100","article-title":"Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling","volume":"100","author":"VI Brown","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1517\/14728222.12.2.209","article-title":"Mammalian target of rapamycin as a therapeutic target in oncology","volume":"12","author":"RT Abraham","year":"2008","journal-title":"Expert Opin Ther Targets"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1182\/blood-2007-03-080796","article-title":"Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase\/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways","volume":"111","author":"J Tamburini","year":"2008","journal-title":"Blood"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1182\/blood-2004-06-2494","article-title":"Antileukemic activity of rapamycin in acute myeloid leukemia","volume":"105","author":"C R\u00e9cher","year":"2005","journal-title":"Blood"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.ceb.2009.10.007","article-title":"mTOR and cancer: many loops in one pathway","volume":"22","author":"A Efeyan","year":"2010","journal-title":"Curr Opin Cell Biol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1158\/1535-7163.MCT-08-0668","article-title":"Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K\/mTOR inhibition","volume":"8","author":"M Breuleux","year":"2009","journal-title":"Mol Cancer Ther"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1200\/JCO.2008.20.0766","article-title":"Targeting the mTOR signaling network for cancer therapy","volume":"27","author":"F Meric-Bernstam","year":"2009","journal-title":"J Clin Oncol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ceb.2009.01.016","article-title":"Optimal targeting of the mTORC1 kinase in human cancer","volume":"21","author":"HA Lane","year":"2009","journal-title":"Curr Opin Cell Biol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"7116","DOI":"10.1158\/1078-0432.CCR-11-0796","article-title":"Novel phosphoinositide 3-kinase\/mTOR dual inhibitor, NVP-BGT226, displays potent growth-inhibitory activity against human head and neck cancer cells in vitro and in vivo","volume":"17","author":"KY Chang","year":"2011","journal-title":"Clin Cancer Res"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1158\/1535-7163.MCT-11-0474","article-title":"Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor","volume":"11","author":"SM Maira","year":"2012","journal-title":"Mol Cancer Ther"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1158\/1535-7163.MCT-08-0017","article-title":"Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase\/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity","volume":"7","author":"SM Maira","year":"2008","journal-title":"Mol Cancer Ther"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1517\/17460441.2011.558079","article-title":"Research and innovation in the development of everolimus for oncology","volume":"6","author":"D Lebwohl","year":"2011","journal-title":"Expert Opin Drug Discov"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.exphem.2008.11.002","article-title":"Long-term culture of primary human lymphoblastic leukemia cells in the absence of serum or hematopoietic growth factors","volume":"37","author":"BA Nijmeijer","year":"2009","journal-title":"Exp Hematol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cancergencyto.2008.05.001","article-title":"Establishment and cytogenetic characterization of a human acute lymphoblastic leukemia cell line (ALL-VG) with ETV6\/ABL1 rearrangement","volume":"185","author":"J Baeumler","year":"2008","journal-title":"Cancer Genet Cytogenet"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"8001","DOI":"10.1128\/MCB.25.18.8001-8008.2005","article-title":"Phosphatidylinositol 3-kinase p85{alpha} subunit-dependent interaction with BCR\/ABL-related fusion tyrosine kinases: molecular mechanisms and biological consequences","volume":"25","author":"SY Ren","year":"2005","journal-title":"Mol Cell Biol"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3109\/08977194.2010.518616","article-title":"Second AKT: the rise of SGK in cancer signalling","volume":"28","author":"MA Bruhn","year":"2010","journal-title":"Growth Factors"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"5424","DOI":"10.1158\/1078-0432.CCR-10-1102","article-title":"Dual inhibition of PI3K and mTORC1\/2 signaling by NVP-BEZ235 as a new therapeutic strategy for acute myeloid leukemia","volume":"16","author":"N Chapuis","year":"2010","journal-title":"Clin Cancer Res"},{"key":"ref43","first-page":"115","article-title":"The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine","volume":"4","author":"EI Ahmad","year":"2011","journal-title":"Onco Targets Ther"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.4161\/cc.3.10.1164","article-title":"Oncogenic mutations of PIK3CA in human cancers","volume":"3","author":"Y Samuels","year":"2004","journal-title":"Cell Cycle"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1038\/nm1636","article-title":"Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia","volume":"13","author":"T Palomero","year":"2007","journal-title":"Nat Med"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/sj.bjc.6604512","article-title":"The transforming mutation E17K\/AKT1 is not a major event in B-cell-derived lymphoid leukaemias","volume":"99","author":"IS Mahmoud","year":"2008","journal-title":"Br J Cancer"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.leukres.2006.04.011","article-title":"Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene","volume":"31","author":"CI M\u00fcller","year":"2007","journal-title":"Leuk Res"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1111\/j.0902-4441.2006.t01-1-EJH2605.x","article-title":"Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia","volume":"77","author":"P Hummerdal","year":"2006","journal-title":"Eur J Haematol"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/j.1600-0609.2009.01350.x","article-title":"Chronic myeloid leukemia and BCR\/ABL signal pathways are not associated with AKT1 pleckstrin homology domain (E17K) mutations","volume":"84","author":"Y He","year":"2010","journal-title":"Eur J Haematol"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.leukres.2007.09.005","article-title":"Resistance to Imatinib Mesylate-induced apoptosis in acute lymphoblastic leukemia is associated with PTEN down-regulation due to promoter hypermethylation","volume":"32","author":"C Montiel-Duarte","year":"2008","journal-title":"Leuk Res"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/j.ctrv.2012.12.002","article-title":"Promise of rapalogues versus mTOR kinase inhibitors in subset specific breast cancer: old targets new hope","volume":"39","author":"P De","year":"2013","journal-title":"Cancer Treat Rev"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"e27509","DOI":"10.1371\/journal.pone.0027509","article-title":"S6K1 and 4E-BP1 are independent regulated and control cellular growth in bladder cancer","volume":"6","author":"R Nawroth","year":"2011","journal-title":"PLOS ONE"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"4268","DOI":"10.1182\/blood-2003-07-2193","article-title":"Phosphoinositide 3-kinase signaling is essential for ABL oncogene-mediated transformation of B-lineage cells","volume":"103","author":"MG Kharas","year":"2004","journal-title":"Blood"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1182\/blood-2008-02-137737","article-title":"AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines","volume":"113","author":"DS Levy","year":"2009","journal-title":"Blood"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"2964","DOI":"10.1182\/blood-2012-08-446096","article-title":"Combined inhibition of PI3K-related DNA damage response kinases and mTORC1 induces apoptosis in MYC-driven B-cell lymphomas","volume":"121","author":"J Shortt","year":"2013","journal-title":"Blood"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0080070","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T00:50:44Z","timestamp":1596847844000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0080070"}},"subtitle":[],"editor":[{"given":"Linda","family":"Bendall","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2013,11,14]]},"references-count":55,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2013,11,14]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0080070","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,11,14]]}}}