QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.044636v1 73/6/1632    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Boehm, A. L. Articles by Grandis, J. R. Search for Related Content PubMed PubMed Citation Articles by Boehm, A. L. Articles by Grandis, J. R.

Combined Targeting of Epidermal Growth Factor Receptor, Signal Transducer and Activator of Transcription-3, and Bcl-X_L Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck

Departments of Pathology (A.L.B., R.S.), Otolaryngology (M.S., M.F., S.M.Y.W., J.R.G.), Pharmacology (D.E.J., J.R.G.), Medicine (D.E.J.), and Biostatistics (W.E.G), University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and Department of Medicine, University of Michigan, Ann Arbor, Michigan (S.W.)

Squamous cell carcinoma of the head and neck (SCCHN) is a leading cause of cancer deaths worldwide. Epidermal growth factor receptor (EGFR), an upstream mediator of signal transducer and activator of transcription (STAT)-3 is overexpressed in a variety of cancers, including SCCHN. Therapies such as monoclonal antibodies and tyrosine kinase inhibitors targeting EGFR have demonstrated limited antitumor efficacy, which may be explained, in part, by persistent STAT3 activation despite EGFR inhibition. STAT3 activation induces expression of target genes in SCCHN, including Bcl-X_L, a mediator of antiapoptotic activity. Bcl-X_L is commonly overexpressed in SCCHN where it correlates with chemoresistance, making it a potential therapeutic target. Targeting the EGFR-STAT3-Bcl-X_L pathway at several levels, including the upstream receptor, the intracellular transcription factor, and the downstream target gene, has not been investigated previously. Using erlotinib, an EGFR-specific reversible tyrosine kinase inhibitor in combination with a STAT3 transcription factor decoy, we found enhanced antitumor effects in vitro and in vivo. The combination of the STAT3 decoy and gossypol, a small molecule targeting Bcl-X_L, also yielded enhanced inhibition of cell proliferation. The triple combination of erlotinib, STAT3 decoy, and gossypol further enhanced cell growth inhibition and apoptosis in vitro, and it down-regulated signaling molecules further downstream of the EGFR-STAT3 signaling pathway, such as cyclin D1. These results suggest that combined targeting of several components of an oncogenic signaling pathway may be an effective therapeutic strategy for SCCHN.

Address correspondence to: Dr. Jennifer Rubin Grandis, Suite 500 Eye and Ear Institute, 203 Lothrop St., University of Pittsburgh, Pittsburgh, PA 15213. E-mail: jgrandis{at}pitt.edu

This article has been cited by other articles:

				P. Koppikar, V. W. Y. Lui, D. Man, S. Xi, R. L. Chai, E. Nelson, A. B.J. Tobey, and J. R. Grandis Constitutive Activation of Signal Transducer and Activator of Transcription 5 Contributes to Tumor Growth, Epithelial-Mesenchymal Transition, and Resistance to Epidermal Growth Factor Receptor Targeting Clin. Cancer Res., December 1, 2008; 14(23): 7682 - 7690. [Abstract] [Full Text] [PDF]