title: Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity.
abstract: OBJECTIVE
  To assess the effects of a novel type 1 insulin-like growth factor receptor (IGF-1R) inhibitor, NVP-AEW541, on cell proliferation and signal transduction of esophageal cancer.
  
  
  METHODS
  Cell proliferation assay and western blot were conducted to assess the antitumor effects of NVP-AEW541. Genetic modification of RAS by expression vector was applied for overexpression of mutant RAS.
  
  
  RESULTS
  More than 2 μmol/l of NVP-AEW541 was required to effectively inhibit the proliferation of esophageal cancer. NVP-AEW541 potently blocked the activation of IGF-1R and protein kinase B (PKB, also known as AKT), but not of mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinases (ERK). Active RAS was not reduced by NVP-AEW541 in esophageal cancer cells TE-1, suggesting that insensitivity of esophageal cancer to NVP-AEW541 is due to the maintained RAS-MAPK activity, which did not arise from RAS mutation. Moreover, the transduction of mutant RAS reduced the sensitivity of TE-1 cells to NVP-AEW541.
  
  
  CONCLUSIONS
  Stimulation of RAS-MAPK pathway is associated with resistance to NVP-AEW541 in esophageal cancer. Combining NVP-AEW541 with inhibitors/antibodies against RAS-MAPK signaling molecules might be more effective for use against esophageal cancer.
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
authors: Xiao-Hong
authors: XH
authors: Bao
authors: Munenori
authors: M
authors: Takaoka
authors: Hui-Fang
authors: HF
authors: Hao
authors: Zhi-Gang
authors: ZG
authors: Wang
authors: Takuya
authors: T
authors: Fukazawa
authors: Tomoki
authors: T
authors: Yamatsuji
authors: Kazufumi
authors: K
authors: Sakurama
authors: Dong-Sheng
authors: DS
authors: Sun
authors: Takeshi
authors: T
authors: Nagasaka
authors: Toshiyoshi
authors: T
authors: Fujiwara
authors: Yoshio
authors: Y
authors: Naomoto
mesh_terms: D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1; D048490:raf Kinases; D018631:ras Proteins; C501177:NVP-AEW541