title: The synergistic interaction of MEK and PI3K inhibitors is modulated by mTOR inhibition.
abstract: BACKGROUND
  Combined targeting of MAPK and PI3K signalling pathways may be necessary for optimal therapeutic activity in cancer. This study evaluated the MEK inhibitors AZD6244 and PD0325901, alone and in combination with the dual mTOR/PI3K inhibitor NVP-BEZ235 or the PI3K inhibitor GDC-0941, in three colorectal cancer cell lines.
  
  
  METHODS
  Growth inhibition, survival and signal transduction were measured using the Sulforhodamine B assay, clonogenicity and western blotting, respectively, in HCT116, HT29 and DLD1 cell lines.
  
  
  RESULTS
  All MEK/PI3K inhibitor combinations exhibited marked synergistic growth inhibition; however, GDC-0941 displayed greater synergy in combination with either MEK inhibitor. NVP-BEZ235 exhibited stronger inhibition of 4EBP1 phosphorylation, and similar inhibition of S6 and AKT phosphorylation, compared with GDC-0941. Both PD0325901 and AZD6244 inhibited ERK phosphorylation, and with MEK/PI3K inhibitor combinations inhibition of S6 phosphorylation was increased. The reduced synergy exhibited by NVP-BEZ235 in combination with MEK inhibitors, compared with GDC-0941, may be due to inhibition of mTOR, and the addition of the mTORC1/2 inhibitor KU0063794 compromised the synergy of GDC-0941:PD0325901 combinations.
  
  
  CONCLUSIONS
  These studies confirm that dual targeting of PI3K and MEK can induce synergistic growth inhibition; however, the combination of specific PI3K inhibitors, rather than dual mTOR/PI3K inhibitors, with MEK inhibitors results in greater synergy.
authors.affiliation: Drug Discovery and Imaging, Newcastle Cancer Centre, Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: E J
authors.initials: EJ
authors.lastname: Haagensen
authors.forename: S
authors.initials: S
authors.lastname: Kyle
authors.forename: G S
authors.initials: GS
authors.lastname: Beale
authors.forename: R J
authors.initials: RJ
authors.lastname: Maxwell
authors.forename: D R
authors.initials: DR
authors.lastname: Newell
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001549:Benzamides; D001562:Benzimidazoles; D004159:Diphenylamine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007191:Indazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C517975:AZD 6244; C541932:Ku 0063794; C506614:mirdametinib; C546842:MTOR protein, human; C531198:dactolisib