Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
de Bono, JS
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<h4>Background</h4>We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents.<h4>Materials and methods</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.
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Tumor Cells, Cultured
Proto-Oncogene Proteins B-raf
MAP Kinase Kinase 1
Protein Kinase Inhibitors
Enzyme-Linked Immunosorbent Assay
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
Class I Phosphatidylinositol 3-Kinases
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
License start date
Annals of oncology : official journal of the European Society for Medical Oncology, 2015, 26 (7), pp. 1504 - 1510
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