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

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

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2827-2834
Number of pages8
JournalAnticancer Research
Volume32
Issue number7
Publication statusPublished - Jul 2012

Fingerprint

Esophageal Neoplasms
Mitogen-Activated Protein Kinase Kinases
Cell Proliferation
NVP-AEW541
Proto-Oncogene Proteins c-akt
IGF Type 1 Receptor
Extracellular Signal-Regulated MAP Kinases
Signal Transduction
Western Blotting
Mutation
Antibodies

Keywords

  • Esophageal cancer
  • IGF-1R
  • NVP-AEW541
  • Ras-MAPK

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bao, X. H., Takaoka, M., Hao, H. F., Wang, Z. G., Fukazawa, T., Yamatsuji, T., ... Naomoto, Y. (2012). Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity. Anticancer Research, 32(7), 2827-2834.

Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity. / Bao, Xiao Hong; Takaoka, Munenori; Hao, Hui Fang; Wang, Zhi Gang; Fukazawa, Takuya; Yamatsuji, Tomoki; Sakurama, Kazufumi; Sun, Dong Sheng; Nagasaka, Takeshi; Fujiwara, Toshiyoshi; Naomoto, Yoshio.

In: Anticancer Research, Vol. 32, No. 7, 07.2012, p. 2827-2834.

Research output: Contribution to journalArticle

Bao, XH, Takaoka, M, Hao, HF, Wang, ZG, Fukazawa, T, Yamatsuji, T, Sakurama, K, Sun, DS, Nagasaka, T, Fujiwara, T & Naomoto, Y 2012, 'Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity', Anticancer Research, vol. 32, no. 7, pp. 2827-2834.
Bao XH, Takaoka M, Hao HF, Wang ZG, Fukazawa T, Yamatsuji T et al. Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity. Anticancer Research. 2012 Jul;32(7):2827-2834.
Bao, Xiao Hong ; Takaoka, Munenori ; Hao, Hui Fang ; Wang, Zhi Gang ; Fukazawa, Takuya ; Yamatsuji, Tomoki ; Sakurama, Kazufumi ; Sun, Dong Sheng ; Nagasaka, Takeshi ; Fujiwara, Toshiyoshi ; Naomoto, Yoshio. / Esophageal cancer exhibits resistance to a novel IGF-1R inhibitor NVP-AEW541 with maintained RAS-MAPK activity. In: Anticancer Research. 2012 ; Vol. 32, No. 7. pp. 2827-2834.
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AB - 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.

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