Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
Date
2015-07Author
Stewart, A
Thavasu, P
de Bono, JS
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Tumor Cells, Cultured
Humans
Neoplasms
Benzamides
Diphenylamine
Proto-Oncogene Proteins B-raf
MAP Kinase Kinase 1
Protein Kinase Inhibitors
Enzyme-Linked Immunosorbent Assay
Signal Transduction
Cell Proliferation
Drug Synergism
Mutation
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
Phosphatidylinositol 3-Kinases
Class I Phosphatidylinositol 3-Kinases
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Language
eng
Date accepted
2015-04-13
License start date
2015-07
Citation
Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by-nc/4.0
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