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dc.contributor.authorStewart, Aen_US
dc.contributor.authorThavasu, Pen_US
dc.contributor.authorde Bono, JSen_US
dc.contributor.authorBanerji, Uen_US
dc.date.accessioned2016-11-23T14:20:17Z
dc.date.issued2015-07en_US
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510en_US
dc.identifier.issn0923-7534en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/263
dc.identifier.eissn1569-8041en_US
dc.identifier.doi10.1093/annonc/mdv188en_US
dc.description.abstractWe aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents.A panel of 20 cell lines was exposed to either the MEK inhibitor, PD0325901, or AKT inhibitor, AKT 1/2 inhibitor. p-ERK and p-S6 ELISAs were used to define degrees of MEK and AKT inhibition, respectively. Growth inhibition to different degrees of MEK and AKT inhibition, either singly or in combination using 96-h sulphorhodamine assays was then studied.A significantly greater growth inhibition was seen in BRAF(M) and PIK3CA(M) cells upon maximal MEK (P = 0.004) and AKT inhibition (P = 0.038), respectively. KRAS(M) and BRAF/PIK3CA/KRAS(WT) cells were not significantly more likely to be sensitive to MEK or AKT inhibition. Significant incremental growth inhibition of the combination of MEK + AKT over either MEK or AKT inhibition alone was seen when MEK + AKT was inhibited maximally and not when sub-maximal inhibition of both MEK + AKT was used (11/20 cell lines versus 1/20 cell lines; P = 0.0012).KRAS(M) cells are likely to benefit from combinations of MEK and AKT inhibitors. Sub-maximally inhibiting both MEK and AKT within a combination, in a majority of instances, does not significantly increase growth inhibition compared with maximally inhibiting MEK or AKT alone and alternative phase I trial designs are needed to clinically evaluate such combinations.en_US
dc.formatPrint-Electronicen_US
dc.format.extent1504 - 1510en_US
dc.languageengen_US
dc.language.isoengen_US
dc.subjectTumor Cells, Cultureden_US
dc.subjectHumansen_US
dc.subjectNeoplasmsen_US
dc.subjectBenzamidesen_US
dc.subjectDiphenylamineen_US
dc.subjectProto-Oncogene Proteins B-rafen_US
dc.subjectMAP Kinase Kinase 1en_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectEnzyme-Linked Immunosorbent Assayen_US
dc.subjectSignal Transductionen_US
dc.subjectCell Proliferationen_US
dc.subjectDrug Synergismen_US
dc.subjectMutationen_US
dc.subjectProto-Oncogene Proteins p21(ras)en_US
dc.subjectProto-Oncogene Proteins c-akten_US
dc.subjectPhosphatidylinositol 3-Kinasesen_US
dc.titleTitration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.en_US
dc.typeJournal Article
dcterms.dateAccepted2015-04-13en_US
rioxxterms.versionofrecord10.1093/annonc/mdv188en_US
rioxxterms.licenseref.startdate2015-07en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncologyen_US
pubs.issue7en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.volume26en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorTurner, Lydiaen_US
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorBanerji, Udaien_US


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