This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jimeno, A. Articles by Hidalgo, M. Search for Related Content PubMed PubMed Citation Articles by Jimeno, A. Articles by Hidalgo, M.

Research Articles: Therapeutics, Targets, and Development

Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer

¹ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and ² Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland

Requests for reprints: Manuel Hidalgo, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University, School of Medicine, The Baunting and Blaustein Cancer Research Building, 1650 Orleans Street, Room 1M89, Baltimore, MD 21231. Phone: 410-502-3543; Fax: 410-614-9006. E-mail: mhidalg1{at}jhmi.edu

Abstract

This study aimed to develop rational combinations of targeted agents against biliary and pancreatic cancers. To this end, we compared the global gene expression profile of biliary cancer cell lines with different degrees of sensibility to the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib using the Affymetrix U133A microarray platform. A set of 32 genes, including genes involved in signal transduction pathways, cell cycle regulation, and angiogenesis, was highly overexpressed in resistant cells. Five of these genes encoded proteins in the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway, a finding that was confirmed by Western blot and immunohistochemistry. Gefitinib failed to inhibit the MAPK pathway in resistant cell lines. Based on these data, we explored the activity of dual treatment with gefitinib in combination with CI-1040, a MAPK inhibitor. This strategy effectively resulted in inhibition of the MAPK signaling pathway and exerted antitumor effects in vitro and in vivo in tumors resistant to each of the agents alone. To further confirm these results, we tested the combined treatment in four tumor xenografts generated from patients with resected pancreatic cancer. Combined treatment was more effective than either single agent alone in this model. This study illustrates the value of global analysis of gene expression to rationally design combinations of mechanistic-based drugs. In addition, the data support the efficacy of combined epidermal growth factor receptor and MAPK inhibitors in biliary and pancreatic cancers, providing the basis to test this combination in the clinic. [Mol Cancer Ther 2007;6(3):1079–88]

Grant support: "Fundacion Caixa Galicia," Spain (B. Rubio-Viqueira); Instituto de Salud Carlos III, Madrid, Spain grant 01/9536 (M.L. Amador); Lee Family; and Viragh Foundation for Pancreas Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ http://www.dCHIP.org

⁴ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/31/06; revised 12/ 2/06; accepted 2/ 1/07.

This article has been cited by other articles:

				A. Jimeno, A. C. Tan, J. Coffa, N.V. Rajeshkumar, P. Kulesza, B. Rubio-Viqueira, J. Wheelhouse, B. Diosdado, W. A. Messersmith, C. Iacobuzio-Donahue, et al. Coordinated Epidermal Growth Factor Receptor Pathway Gene Overexpression Predicts Epidermal Growth Factor Receptor Inhibitor Sensitivity in Pancreatic Cancer Cancer Res., April 15, 2008; 68(8): 2841 - 2849. [Abstract] [Full Text] [PDF]