title: Titration of signalling output: insights into clinical combinations of MEK and AKT inhibitors.
abstract: BACKGROUND
  We aimed to understand the relative contributions of inhibiting MEK and AKT on cell growth to guide combinations of these agents.
  
  
  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.
authors.affiliation: Division of Cancer Therapeutics/Division of Clinical Studies, The Institute of Cancer Research, London.
authors.forename: A
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Division of Cancer Therapeutics/Division of Clinical Studies, The Institute of Cancer Research, London.
authors.forename: P
authors.initials: P
authors.lastname: Thavasu
authors.affiliation: Division of Cancer Therapeutics/Division of Clinical Studies, The Institute of Cancer Research, London The Royal Marsden, London, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Division of Cancer Therapeutics/Division of Clinical Studies, The Institute of Cancer Research, London The Royal Marsden, London, UK udai.banerji@icr.ac.uk.
authors.forename: U
authors.initials: U
authors.lastname: Banerji
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D058534:Class I Phosphatidylinositol 3-Kinases; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); C117307:KRAS protein, human; C506614:mirdametinib; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C482125:MAP2K1 protein, human
keywords: AKT inhibitor; MEK inhibitor; combination