title: Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037.
abstract: OBJECTIVE
  Tumours frequently have defects in multiple oncogenic pathways, e.g. MAPK and PI3K signalling pathways, and combinations of targeted therapies may be required for optimal activity. This study evaluated the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037, as single agents and in combination, in colorectal carcinoma cell lines and tumour xenograft-bearing mice.
  
  
  METHODS
  In vitro growth inhibition, survival and signal transduction were measured using the Sulforhodamine B, clonogenic and Western blotting assays, respectively, in HCT116 and HT29 cell lines. In vivo anti-tumour efficacy and pharmacokinetic properties were assessed in HCT116 and HT29 human colorectal cancer xenograft tumour-bearing mice.
  
  
  RESULTS
  The combination of WX-554 and WX-037 exhibited marked synergistic growth inhibition in vitro, which was associated with increased cytotoxicity and enhanced inhibition of ERK and S6 phosphorylation, compared to either agent alone. Pharmacokinetic analyses indicated that there was no PK interaction between the two drugs at low doses, but that at higher doses, WX-037 may delay the tumour uptake of WX-554. In vivo efficacy studies revealed that the combination of WX-037 and WX-554 was non-toxic and exhibited marked tumour growth inhibition greater than observed with either agent alone.
  
  
  CONCLUSIONS
  These studies show for the first time that combination treatment with the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037 can induce synergistic growth inhibition in vitro, which translates into enhanced anti-tumour efficacy in vivo.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Haagensen
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Wilex AG, Grillparzerstrasse 18, 81675, Munich, Germany.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schmalix
authors.affiliation: UCB Pharma Ltd, 208 Bath Road, Slough, SL1 3WE, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Payne
authors.affiliation: UCB Pharma Ltd, 208 Bath Road, Slough, SL1 3WE, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Kevorkian
authors.affiliation: UCB Pharma Ltd, 208 Bath Road, Slough, SL1 3WE, UK.
authors.forename: Rodger A
authors.initials: RA
authors.lastname: Allen
authors.affiliation: Wilex AG, Grillparzerstrasse 18, 81675, Munich, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Bevan
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Maxwell
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. herbie.newell@ncl.ac.uk.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004357:Drug Synergism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Combination; MEK; PI3K; Synergy; Colorectal cancer