title: Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells.
abstract: BACKGROUND
  The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized.
  
  
  METHODS
  LS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts.
  
  
  RESULTS
  PP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor.
  
  
  CONCLUSIONS
  Taken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors.
authors.affiliation: Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Pavillon 4, Av, de Beaumont, 1011 Lausanne, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Blaser
authors.forename: Laurent
authors.initials: L
authors.lastname: Waselle
authors.forename: Anne
authors.initials: A
authors.lastname: Dormond-Meuwly
authors.forename: Marc
authors.initials: M
authors.lastname: Dufour
authors.forename: Didier
authors.initials: D
authors.lastname: Roulin
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011687:Purines; D011804:Quinolines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C572919:PP242; C531198:dactolisib; D020123:Sirolimus