Show simple item record

dc.contributor.authorStewart, A
dc.contributor.authorThavasu, P
dc.contributor.authorde Bono, JS
dc.contributor.authorBanerji, U
dc.date.accessioned2016-11-23T14:20:17Z
dc.date.issued2015-07-01
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/263
dc.identifier.eissn1569-8041
dc.identifier.doi10.1093/annonc/mdv188
dc.description.abstractBACKGROUND: We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
dc.formatPrint-Electronic
dc.format.extent1504 - 1510
dc.languageeng
dc.language.isoeng
dc.publisherOXFORD UNIV PRESS
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0
dc.subjectTumor Cells, Cultured
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectBenzamides
dc.subjectDiphenylamine
dc.subjectProto-Oncogene Proteins B-raf
dc.subjectMAP Kinase Kinase 1
dc.subjectProtein Kinase Inhibitors
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectSignal Transduction
dc.subjectCell Proliferation
dc.subjectDrug Synergism
dc.subjectMutation
dc.subjectProto-Oncogene Proteins p21(ras)
dc.subjectProto-Oncogene Proteins c-akt
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectClass I Phosphatidylinositol 3-Kinases
dc.titleTitration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
dc.typeJournal Article
dcterms.dateAccepted2015-04-13
rioxxterms.versionofrecord10.1093/annonc/mdv188
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by-nc/4.0
rioxxterms.licenseref.startdate2015-07
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue7
pubs.notesNot known
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.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.publication-statusPublished
pubs.volume26
pubs.embargo.termsNot known
icr.researchteamClinical Pharmacology – Adaptive Therapy
icr.researchteamMedicine Drug Development Unit (de Bono)
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorDe Bono, Johann
dc.contributor.icrauthorBanerji, Udai


Files in this item

Thumbnail
Thumbnail

This item appears in the following collection(s)

Show simple item record

https://creativecommons.org/licenses/by-nc/4.0
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc/4.0