{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:03:11Z","timestamp":1791295391549,"version":"4.1.0"},"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2012,11,21]],"date-time":"2012-11-21T00:00:00Z","timestamp":1353456000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0050005","type":"journal-article","created":{"date-parts":[[2012,11,21]],"date-time":"2012-11-21T22:59:27Z","timestamp":1353538767000},"page":"e50005","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":54,"title":["Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3K\/Akt and MEK\/ERK Pathway"],"prefix":"10.1371","volume":"7","author":[{"given":"Vijay","family":"Ramakrishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Kimlinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Haug","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Utkarsh","family":"Painuly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Wellik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Halling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Vincent","family":"Rajkumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaji","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2012,11,21]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/nrclinonc.2011.63","article-title":"Treatment of multiple myeloma","volume":"8","author":"SV Rajkumar","year":"2011","journal-title":"Nat Rev Clin Oncol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/leu.2011.196","article-title":"Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study","volume":"26","author":"SK Kumar","year":"2012","journal-title":"Leukemia"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.biochem.67.1.481","article-title":"Phosphoinositide kinases","volume":"67","author":"DA Fruman","year":"1998","journal-title":"Annu Rev Biochem"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"6541","DOI":"10.1002\/j.1460-2075.1996.tb01045.x","article-title":"Mechanism of activation of protein kinase B by insulin and IGF-1","volume":"15","author":"DR Alessi","year":"1996","journal-title":"Embo J"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"21920","DOI":"10.1074\/jbc.271.36.21920","article-title":"Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation","volume":"271","author":"AD Kohn","year":"1996","journal-title":"J Biol Chem"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/S0092-8674(00)80595-4","article-title":"Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor","volume":"96","author":"A Brunet","year":"1999","journal-title":"Cell"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1126\/science.278.5338.687","article-title":"Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt","volume":"278","author":"L del Peso","year":"1997","journal-title":"Science"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"re15","DOI":"10.1126\/stke.2122003re15","article-title":"TOR signaling","volume":"2003","author":"TE Harris","year":"2003","journal-title":"Sci STKE"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.ccr.2009.03.020","article-title":"Ligand-independent HER2\/HER3\/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941","volume":"15","author":"TT Junttila","year":"2009","journal-title":"Cancer Cell"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"5800","DOI":"10.1128\/MCB.19.8.5800","article-title":"Akt\/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria","volume":"19","author":"SG Kennedy","year":"1999","journal-title":"Mol Cell Biol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1128\/MCB.17.3.1595","article-title":"Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt","volume":"17","author":"G Kulik","year":"1997","journal-title":"Mol Cell Biol"},{"key":"ref12","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":"RJ Shaw","year":"2004","journal-title":"Cancer Cell"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature02369","article-title":"Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy","volume":"428","author":"HG Wendel","year":"2004","journal-title":"Nature"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"23433","DOI":"10.1074\/jbc.C500169200","article-title":"Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency","volume":"280","author":"X Long","year":"2005","journal-title":"J Biol Chem"},{"key":"ref15","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":"Y Sancak","year":"2007","journal-title":"Mol Cell"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.molcel.2010.09.026","article-title":"Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress","volume":"40","author":"S Sengupta","year":"2010","journal-title":"Mol Cell"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"13571","DOI":"10.1073\/pnas.202476899","article-title":"Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling","volume":"99","author":"AR Tee","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.leukres.2005.07.008","article-title":"Analysis of PTEN deletions and mutations in multiple myeloma","volume":"30","author":"H Chang","year":"2006","journal-title":"Leuk Res"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.leukres.2009.11.018","article-title":"Hotspot mutations of PIK3CA and AKT1 genes are absent in multiple myeloma","volume":"34","author":"SI Ismail","year":"2010","journal-title":"Leuk Res"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"5991","DOI":"10.1038\/sj.onc.1204833","article-title":"Biologic sequelae of interleukin-6 induced PI3-K\/Akt signaling in multiple myeloma","volume":"20","author":"T Hideshima","year":"2001","journal-title":"Oncogene"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"3126","DOI":"10.1182\/blood-2002-08-2640","article-title":"Downstream effectors of oncogenic ras in multiple myeloma cells","volume":"101","author":"L Hu","year":"2003","journal-title":"Blood"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"5673","DOI":"10.1038\/sj.onc.1205664","article-title":"Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1\/Akt signaling in human multiple myeloma cells: therapeutic implications","volume":"21","author":"CS Mitsiades","year":"2002","journal-title":"Oncogene"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"15712","DOI":"10.1074\/jbc.M200043200","article-title":"Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6","volume":"277","author":"Y Shi","year":"2002","journal-title":"J Biol Chem"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.1182\/blood-2010-05-284422","article-title":"Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival","volume":"117","author":"T Steinbrunn","year":"2011","journal-title":"Blood"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1016\/j.leukres.2009.01.039","article-title":"Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma","volume":"33","author":"SS Farag","year":"2009","journal-title":"Leuk Res"},{"key":"ref26","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":"RC Hresko","year":"2005","journal-title":"J Biol Chem"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1\u20132 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins","volume":"166","author":"LS Harrington","year":"2004","journal-title":"J Cell Biol"},{"key":"ref28","first-page":"1781","article-title":"Cyclic adenosine-3\u2032,5\u2032-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma","volume":"3","author":"NL Krett","year":"1997","journal-title":"Clin Cancer Res"},{"key":"ref29","first-page":"5125","article-title":"Characterization of a new drug-resistant human myeloma cell line that expresses P-glycoprotein","volume":"46","author":"WS Dalton","year":"1986","journal-title":"Cancer Res"},{"key":"ref30","first-page":"995","article-title":"Development and characterization of a melphalan-resistant human multiple myeloma cell line","volume":"51","author":"WT Bellamy","year":"1991","journal-title":"Cancer Res"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/ijc.2910360217","article-title":"Two distinct human myeloma cell lines originating from one patient with myeloma","volume":"36","author":"S Katagiri","year":"1985","journal-title":"Int J Cancer"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/leu.2011.192","article-title":"MRK003, a gamma-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin&apos;s lymphoma","volume":"26","author":"V Ramakrishnan","year":"2012","journal-title":"Leukemia"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1002\/ajh.21785","article-title":"TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells","volume":"85","author":"V Ramakrishnan","year":"2010","journal-title":"Am J Hematol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1038\/onc.2009.403","article-title":"Sorafenib, a dual Raf kinase\/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs","volume":"29","author":"V Ramakrishnan","year":"2010","journal-title":"Oncogene"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"TC Chou","year":"1984","journal-title":"Adv Enzyme Regul"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1182\/blood-2005-08-3434","article-title":"Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells","volume":"107","author":"T Hideshima","year":"2006","journal-title":"Blood"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1182\/blood-2003-06-1984","article-title":"BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone","volume":"103","author":"J Moreaux","year":"2004","journal-title":"Blood"},{"key":"ref38","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":"R Zoncu","year":"2011","journal-title":"Nat Rev Mol Cell Biol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/CAD.0b013e32834c8683","article-title":"Simultaneous targeting of PI3K and mTOR with NVP-BGT226 is highly effective in multiple myeloma","volume":"23","author":"P Baumann","year":"2012","journal-title":"Anticancer Drugs"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1158\/1535-7163.MCT-09-0763","article-title":"Dual inhibition of akt\/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma","volume":"9","author":"D Cirstea","year":"2010","journal-title":"Mol Cancer Ther"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.1182\/blood-2010-05-285726","article-title":"Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor","volume":"116","author":"B Hoang","year":"2010","journal-title":"Blood"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"6860","DOI":"10.1182\/blood-2011-03-342394","article-title":"Defining the role of TORC1\/2 in multiple myeloma","volume":"118","author":"P Maiso","year":"2011","journal-title":"Blood"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"5835","DOI":"10.1158\/0008-5472.CAN-08-4285","article-title":"Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase\/mammalian target of rapamycin inhibitor NVP-BEZ235","volume":"69","author":"DW McMillin","year":"2009","journal-title":"Cancer Res"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1111\/j.1365-2141.2007.06714.x","article-title":"Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells","volume":"138","author":"T Hideshima","year":"2007","journal-title":"Br J Haematol"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"4243","DOI":"10.1200\/JCO.2010.33.9788","article-title":"Perifosine Plus Bortezomib and Dexamethasone in Patients With Relapsed\/Refractory Multiple Myeloma Previously Treated With Bortezomib: Results of a Multicenter Phase I\/II Trial","volume":"29","author":"PG Richardson","year":"2011","journal-title":"J Clin Oncol"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1007\/s11912-009-0016-4","article-title":"Perifosine: update on a novel Akt inhibitor","volume":"11","author":"JJ Gills","year":"2009","journal-title":"Curr Oncol Rep"},{"key":"ref47","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":"A Carracedo","year":"2008","journal-title":"J Clin Invest"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1074\/jbc.M110.159046","article-title":"ERK1\/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1)","volume":"286","author":"A Carriere","year":"2011","journal-title":"J Biol Chem"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"4649","DOI":"10.1158\/1078-0432.CCR-09-0317","article-title":"In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models","volume":"15","author":"KP Hoeflich","year":"2009","journal-title":"Clin Cancer Res"},{"key":"ref50","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":"S Zimmermann","year":"1999","journal-title":"Science"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2005.06.009","article-title":"Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin","volume":"19","author":"Q Ding","year":"2005","journal-title":"Mol Cell"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ccr.2010.10.031","article-title":"AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity","volume":"19","author":"S Chandarlapaty","year":"2011","journal-title":"Cancer Cell"}],"container-title":["PLoS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0050005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T20:06:07Z","timestamp":1643659567000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0050005"}},"subtitle":[],"editor":[{"given":"Rakesh K.","family":"Srivastava","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2012,11,21]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2012,11,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0050005","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,11,21]]}}}