Received for publication January 3, 2008.
Revised March 5, 2008.
Accepted for publication March 6, 2008.

Combined Targeting of EGFR, STAT3, and Bcl-X_L Enhances Antitumor Effects in Squamous Cell Carcinoma of the Head and Neck

Abstract

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-3 (STAT3) is over-expressed 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 anti-apoptotic activity. Bcl-X_L is commonly over-expressed 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 previously investigated. 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 downregulated 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.

Key words: Stat activated transcriptional events, Fluorescence techniques, Apoptosis, Overexpression, Transcription targets

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