dc.contributor.author | Stewart, A | |
dc.contributor.author | Thavasu, P | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Banerji, U | |
dc.date.accessioned | 2016-11-23T14:20:17Z | |
dc.date.issued | 2015-07-01 | |
dc.identifier.citation | Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510 | |
dc.identifier.issn | 0923-7534 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/263 | |
dc.identifier.eissn | 1569-8041 | |
dc.identifier.doi | 10.1093/annonc/mdv188 | |
dc.description.abstract | BACKGROUND: 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.format | Print-Electronic | |
dc.format.extent | 1504 - 1510 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | OXFORD UNIV PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0 | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Humans | |
dc.subject | Neoplasms | |
dc.subject | Benzamides | |
dc.subject | Diphenylamine | |
dc.subject | Proto-Oncogene Proteins B-raf | |
dc.subject | MAP Kinase Kinase 1 | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Enzyme-Linked Immunosorbent Assay | |
dc.subject | Signal Transduction | |
dc.subject | Cell Proliferation | |
dc.subject | Drug Synergism | |
dc.subject | Mutation | |
dc.subject | Proto-Oncogene Proteins p21(ras) | |
dc.subject | Proto-Oncogene Proteins c-akt | |
dc.subject | Phosphatidylinositol 3-Kinases | |
dc.subject | Class I Phosphatidylinositol 3-Kinases | |
dc.title | Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2015-04-13 | |
rioxxterms.versionofrecord | 10.1093/annonc/mdv188 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by-nc/4.0 | |
rioxxterms.licenseref.startdate | 2015-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Annals of oncology : official journal of the European Society for Medical Oncology | |
pubs.issue | 7 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 26 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
icr.researchteam | Medicine Drug Development Unit (de Bono) | |
icr.researchteam | Prostate Cancer Targeted Therapy Group | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Banerji, Udai | |