Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
Date
2015-07-01Author
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
Publisher
OXFORD UNIV PRESS
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by-nc/4.0
Related items
Showing items related by title, author, creator and subject.
-
A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours.
Jamieson, D; Griffin, MJ; Sludden, J; Drew, Y; Cresti, N; et al. (ELSEVIER SCI LTD, 2016-11-01)PURPOSE: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, ... -
Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors.
Whittaker, SR; Cowley, GS; Wagner, S; Luo, F; Root, DE; et al. (AMER ASSOC CANCER RESEARCH, 2015-12-01)RAF and MEK inhibitors are effective in BRAF-mutant melanoma but not in BRAF-mutant colorectal cancer. To gain additional insights into this difference, we performed a genome-scale pooled shRNA enhancer screen in a ... -
Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2.
Annibaldi, A; Wicky John, S; Vanden Berghe, T; Swatek, KN; Ruan, J; et al. (CELL PRESS, 2018-02-15)Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains ...