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Anticancer Res. 2012 Jul;32(7):2827-34.

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

Author information

1
Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

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 ╬╝mol/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.

PMID:
22753744
[Indexed for MEDLINE]

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