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dc.contributor.authorWeisberg, Ellen
dc.contributor.authorLiu, Qingsong
dc.contributor.authorZhang, Xin
dc.contributor.authorNelson, Erik
dc.contributor.authorSattler, Martin
dc.contributor.authorLiu, Feiyang
dc.contributor.authorNicolais, Maria
dc.contributor.authorZhang, Jianming
dc.contributor.authorMitsiades, Constantine S
dc.contributor.authorSmith, Robert Walsh
dc.contributor.authorStone, Richard
dc.contributor.authorGalinsky, Ilene
dc.contributor.authorNonami, Atsushi
dc.contributor.authorGriffin, James D.
dc.contributor.authorGray, Nathanael
dc.date.accessioned2013-04-26T17:54:11Z
dc.date.issued2013
dc.identifier.citationWeisberg, Ellen, Qingsong Liu, Xin Zhang, Erik Nelson, Martin Sattler, Feiyang Liu, Maria Nicolais, et al. 2013. Selective akt inhibitors synergize with tyrosine kinase inhibitors and effectively override stroma-associated cytoprotection of mutant flt3-positive aml cells. PLoS ONE 8(2): e56473.en_US
dc.identifier.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10589791
dc.description.abstractObjectives: Tyrosine kinase inhibitor (TKI)-treated acute myeloid leukemia (AML) patients commonly show rapid and significant peripheral blood blast cell reduction, however a marginal decrease in bone marrow blasts. This suggests a protective environment and highlights the demand for a better understanding of stromal:leukemia cell communication. As a strategy to improve clinical efficacy, we searched for novel agents capable of potentiating the stroma-diminished effects of TKI treatment of mutant FLT3-expressing cells. Methods: We designed a combinatorial high throughput drug screen using well-characterized kinase inhibitor-focused libraries to identify novel kinase inhibitors capable of overriding stromal-mediated resistance to TKIs, such as PKC412 and AC220. Standard liquid culture proliferation assays, cell cycle and apoptosis analysis, and immunoblotting were carried out with cell lines or primary AML to validate putative candidates from the screen and characterize the mechanism(s) underlying observed synergy. Results and Conclusions Our study led to the observation of synergy between selective Akt inhibitors and FLT3 inhibitors against mutant FLT3-positive AML in either the absence or presence of stroma. Our findings are consistent with evidence that Akt activation is characteristic of mutant FLT3-transformed cells, as well as observed residual Akt activity following FLT3 inhibitor treatment. In conclusion, our study highlights the potential importance of Akt as a signaling factor in leukemia survival, and supports the use of the co-culture chemical screen to identify agents able to potentiate TKI anti-leukemia activity in a cytoprotective microenvironment.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0056473en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578845/pdf/en_US
dash.licenseLAA
dc.subjectBiologyen_US
dc.subjectGeneticsen_US
dc.subjectCancer Geneticsen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectMembrane Receptor Signalingen_US
dc.subjectSignaling Pathwaysen_US
dc.subjectCell Deathen_US
dc.subjectMedicineen_US
dc.subjectHematologyen_US
dc.subjectHematologic Cancers and Related Disordersen_US
dc.subjectOncologyen_US
dc.subjectBasic Cancer Researchen_US
dc.subjectCancer Treatmenten_US
dc.subjectCancers and Neoplasmsen_US
dc.titleSelective Akt Inhibitors Synergize with Tyrosine Kinase Inhibitors and Effectively Override Stroma-Associated Cytoprotection of Mutant FLT3-Positive AML Cellsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorGriffin, James D.
dc.date.available2013-04-26T17:54:11Z
dc.identifier.doi10.1371/journal.pone.0056473*
dash.authorsorderedfalse
dash.contributor.affiliatedLiu, Qingsong
dash.contributor.affiliatedSmith, Robert Walsh
dash.contributor.affiliatedZhang, Xin
dash.contributor.affiliatedNonami, Atsushi
dash.contributor.affiliatedZhang, Jianming
dash.contributor.affiliatedGriffin, James
dash.contributor.affiliatedMitsiades, Constantine
dash.contributor.affiliatedWeisberg, Ellen
dash.contributor.affiliatedStone, Richard
dash.contributor.affiliatedGray, Nathanael
dash.contributor.affiliatedSattler, Martin
dash.contributor.affiliatedNelson, Erik


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