title: Gastric cancer growth control by BEZ235 in vivo does not correlate with PI3K/mTOR target inhibition but with [18F]FLT uptake.
abstract: OBJECTIVE
  In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo.
  
  
  METHODS
  Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET).
  
  
  RESULTS
  In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [(18)F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET.
  
  
  CONCLUSIONS
  In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Fuereder
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Pamina
authors.initials: P
authors.lastname: Pflegerl
authors.forename: Agnes
authors.initials: A
authors.lastname: Jaeger-Lansky
authors.forename: Doris
authors.initials: D
authors.lastname: Hoeflmayer
authors.forename: Sabine
authors.initials: S
authors.lastname: Strommer
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.forename: Johannes
authors.initials: J
authors.lastname: Werzowa
authors.forename: Michael
authors.initials: M
authors.lastname: Hejna
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Volker
authors.initials: V
authors.lastname: Wacheck
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D019275:Radiopharmaceuticals; D058570:TOR Serine-Threonine Kinases; C002854:alovudine; C531198:dactolisib