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Research Articles: Therapeutics, Targets, and Development

Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer

Departments of ¹ Otolaryngology and ² Pharmacology, University of Pittsburgh School of Medicine and ³ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; ⁴ Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁵ Department of Medicine, Emory University, Atlanta, Georgia; and ⁶ Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong

Requests for reprints: Jennifer Rubin Grandis, Room 105, The Eye and Ear Institute, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-647-5280; Fax: 412-647-0108. E-mail: jgrandis{at}pitt.edu

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho–c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer. [Mol Cancer Ther 2007;6(4):1414–24]

Grant support: NIH grants R01 CA098372-01 (J.R. Grandis), P50 CA097190-01A1 (J.R. Grandis), and U01 CA101244 (D. Shin).

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.

⁷ http://www.fda.gov/cder/drug/infopage/erbitux/default.htm

Received 11/ 3/06; revised 1/22/07; accepted 2/19/07.

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