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Research Articles: Therapeutics, Targets, and Development

Expression of epidermal growth factor (EGF)/transforming growth factor- by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice

Departments of ¹ Cancer Biology, ² Radiation Oncology, ³ Biostatistics and Applied Mathematics, ⁴ Thoracic/Head and Neck Medical Oncology, and ⁵ Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Roy S. Herbst, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-1220. E-mail: rherbst{at}mdanderson.org

Abstract

Epidermal growth factor receptor (EGFR) has been extensively targeted in the treatment of non–small cell lung cancer, producing responses in a small number of patients. To study the role of ligand expression in mediating response to EGFR antagonism, we injected NCI-H441 [EGFR and EGF/transforming growth factor- (TGF-) positive] or PC14-PE6 (EGFR positive and EGF/TGF- negative) human lung adenocarcinoma cells into the lungs of nude mice. We randomized the mice to receive treatment with the EGFR tyrosine kinase inhibitors gefitinib or AEE788 or vehicle. Treatment of mice bearing NCI-H441 but not PC14-PE6 lung tumors resulted in a significant reduction in primary tumor growth, pleural effusion, and lymph node metastasis. Immunohistochemical analyses revealed that NCI-H441 and PC14-PE6 cells expressed EGFR but that the expression of EGF/TGF- was high in NCI-H441 cells and very low in PC14-PE6 cells. Consequently, EGFR was activated in both tumor and tumor-associated endothelial cells in the NCI-H441 tumors but not in the PC14-PE6 tumors. Antagonism of EGFR signaling by treatment of mice with AEE788 decreased proliferation and increased apoptosis of both tumor cells and tumor-associated endothelial cells in NCI-H441 tumors but not in PC14-PE6 tumors. However, after transfection of PC14-PE6 cells with TGF-, lung tumors derived from the transfected cells expressed and activated EGFR in both tumor and tumor-associated endothelial cells and tumors responded to treatment with AEE788. Collectively, these results strongly suggest that the response of human lung cancers growing orthotopically in mice to the inhibition of EGFR signaling is determined by ligand (EGF/TGF-) expression by tumor cells. Our findings provide an additional explanation for the susceptibility of lung cancers to treatment with EGFR tyrosine kinase inhibitors. [Mol Cancer Ther 2007;6(10):2652–63]

Grant support: Cancer Center Support (Core) grant CA16672 and Department of Defense TARGET of Lung Cancer grant DAMD 17-02-1-0706 (R.S. Herbst and M.S. O'Reilly).

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.

Received 12/ 7/06; revised 7/ 8/07; accepted 8/30/07.

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