Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity.

Abstract

AIM:

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.

MATERIALS AND 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.

CONCLUSION:

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: Xiao-Hong Bao, Munenori Takaoka, Hui-Fang Hao, Zhi-Gang Wang, Takuya Fukazawa, Tomoki Yamatsuji, Kazufumi Sakurama, Dong-Sheng Sun, Takeshi Nagasaka, Toshiyoshi Fujiwara, Yoshio Naomoto
• Journal: Anticancer research (Anticancer Res) Vol. 32 Issue 7 Pg. 2827-34 (Jul 2012) ISSN: 1791-7530 [Electronic] Greece
• PMID: 22753744 (Publication Type: Journal Article)

Chemical References

• NVP-AEW541
• Phosphoinositide-3 Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt
• raf Kinases
• Mitogen-Activated Protein Kinases
• ras Proteins

Topics

• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Esophageal Neoplasms (drug therapy, enzymology, pathology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, biosynthesis, metabolism)
• raf Kinases (antagonists & inhibitors, metabolism)
• ras Proteins (antagonists & inhibitors, metabolism)