This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Zhou, Y. Articles by Brattain, M. G. Search for Related Content PubMed PubMed Citation Articles by Zhou, Y. Articles by Brattain, M. G.

Blockade of EGFR and ErbB2 by the Novel Dual EGFR and ErbB2 Tyrosine Kinase Inhibitor GW572016 Sensitizes Human Colon Carcinoma GEO Cells to Apoptosis

Departments of ¹ Pharmacology and Therapeutics and ² Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York and ³ Department of Medicine, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Michael G. Brattain, Department of Molecular Pharmacology and Cancer Therapeutics, Elm and Carlton Streets, Buffalo, NY 14263. Phone: 716-845-3044; Fax: 716-845-4437; E-mail: yunfei.zhou{at}roswellpark.org.

Coexpression of the epidermal growth factor receptor (EGFR) family receptors is found in a subset of colon cancers, which may cooperatively promote cancer cell growth and survival, as heterodimerization is known to provide for diversification of signal transduction. Recently, efforts have been made to develop novel 4-anilinoquinazoline and pyridopyrimidine derivatives to inhibit EGFR and ErbB2 kinases simultaneously. In this study, we tested the efficacy of a novel reversible dual inhibitor GW572016 compared with the selective EGFR and ErbB2 tyrosine kinase inhibitors (TKI) AG1478 and AG879 and their combination, using the human colon adenocarcinoma GEO mode. GEO cells depend on multiple ErbB receptors for aberrant growth. A synergistic effect on inhibition of cell proliferation associated with induction of apoptosis was observed from the combination of AG1478 and AG879. Compared with AG1478 or AG879, the single TKI compound GW572016 was a more potent inhibitor of GEO cell proliferation and was able to induce apoptosis at lower concentrations. Western blot analysis revealed that AG1478 and AG879 were unable to suppress both EGFR and ErbB2 activation as well as the downstream mitogen-activated protein kinase (MAPK) and AKT pathways as single agents. In contrast, GW572016 suppressed the activation of EGFR, ErbB2, MAPK, and AKT in a concentration-dependent manner. Finally, in vivo studies showed that GW572016 treatment efficiently blocked GEO xenograft growth at a dose range of 30 to 200 mg/kg with a twice-daily schedule. In summary, our study indicates that targeting both EGFR and ErbB2 simultaneously could enhance therapy over that of single agents directed at EGFR or ErbB2 in cancers that can be identified as being primarily heterodimer-dependent. (Cancer Res 2006; 66(1): 404-11)

This article has been cited by other articles:

				E. Nilsson, G. Dole, and M. K Skinner Neurotrophin NT3 promotes ovarian primordial to primary follicle transition Reproduction, October 1, 2009; 138(4): 697 - 707. [Abstract] [Full Text] [PDF]

				Y. P. Hu, S. B. Patil, M. Panasiewicz, W. Li, J. Hauser, L. E. Humphrey, and M. G. Brattain Heterogeneity of Receptor Function in Colon Carcinoma Cells Determined by Cross-talk between Type I Insulin-like Growth Factor Receptor and Epidermal Growth Factor Receptor Cancer Res., October 1, 2008; 68(19): 8004 - 8013. [Abstract] [Full Text] [PDF]

				A. P. Martin, A. Miller, L. Emad, M. Rahmani, T. Walker, C. Mitchell, M. P. Hagan, M. A. Park, A. Yacoub, P. B. Fisher, et al. Lapatinib Resistance in HCT116 Cells Is Mediated by Elevated MCL-1 Expression and Decreased BAK Activation and Not by ERBB Receptor Kinase Mutation Mol. Pharmacol., September 1, 2008; 74(3): 807 - 822. [Abstract] [Full Text] [PDF]

				H.-P. Kim, S.-W. Han, S.-H. Kim, S.-A. Im, D.-Y. Oh, Y.-J. Bang, and T.-Y. Kim Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells Mol. Cancer Ther., March 1, 2008; 7(3): 607 - 615. [Abstract] [Full Text] [PDF]

				S. L. Emanuel, T. V. Hughes, M. Adams, C. A. Rugg, A. Fuentes-Pesquera, P. J. Connolly, N. Pandey, S. Moreno-Mazza, J. Butler, V. Borowski, et al. Cellular and in Vivo Activity of JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier and Displays Efficacy against Intracranial Tumors Mol. Pharmacol., February 1, 2008; 73(2): 338 - 348. [Abstract] [Full Text] [PDF]

				L. V. Sequist Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer Oncologist, March 1, 2007; 12(3): 325 - 330. [Abstract] [Full Text] [PDF]

				A. Rajput, A. P. Koterba, J. I. Kreisberg, J. M. Foster, J. K.V. Willson, and M. G. Brattain A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo Cancer Res., January 15, 2007; 67(2): 665 - 673. [Abstract] [Full Text] [PDF]

				B. Moy and P. E. Goss Lapatinib: Current Status and Future Directions in Breast Cancer Oncologist, November 1, 2006; 11(10): 1047 - 1057. [Abstract] [Full Text] [PDF]

				T.-C. Chou Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies Pharmacol. Rev., September 1, 2006; 58(3): 621 - 681. [Abstract] [Full Text] [PDF]