The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinomas of the head and neck (SCCHN) where EGFR expression levels in the tumor correlate with decreased survival. The EGFR monoclonal antibody, cetuximab, was FDA-approved in 2006 for the treatment of SCCHN and is the first new drug for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited, underscoring the importance of elucidating the mechanisms of persistent tumor growth in the setting of EGFR blockade. We have accumulated extensive evidence that EGFR-mediated activation of selected Signal Transducers and Activators of Transcription (STATs) and Src family kinases contribute to SCCHN growth and survival. We recently reported that a mutant EGFR, EGFRvIII is expressed in up to 40% of SCCHN where EGFRvIII is associated with therapeutic resistance, including resistance to cetuximab. Therefore, we propose to test the overall hypothesis that the loss of growth control in SCCHN is mediated by aberrant EGFR signaling though both mutant and wild-type receptors involving selective activation of STAT proteins and/or Src kinases, with the ultimate aim of designing novel treatment strategies to target these pathways. To accomplish the goals of this proposal, we will: 1) determine the role of Src kinases in EGFR-mediated and EGFR-independent growth pathways in SCCHN;2) elucidate the contribution of STAT5 activation to SCCHN progression and response to EGFR blockade;and 3) determine the role of STAT and Src signaling in mediating the oncogenic properties of EGFRvIII in SCCHN.
The proposed studies will elucidate the mechanisms of resistance to EGFR targeting strategies in preclinical models of squamous cell carcinoma of the head and neck. In addition, we will test the hypothesis that STATs, Src family kinases and EGFRvIII contribute to cetuximab resistance in 2 SCCHN patient cohorts.
|Pollock, Netanya I; Grandis, Jennifer R (2015) HER2 as a therapeutic target in head and neck squamous cell carcinoma. Clin Cancer Res 21:526-33|
|Lui, Vivian Wai Yan; Peyser, Noah D; Ng, Patrick Kwok-Shing et al. (2014) Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A 111:1114-9|
|Li, Hua; Wawrose, John S; Gooding, William E et al. (2014) Genomic analysis of head and neck squamous cell carcinoma cell lines and human tumors: a rational approach to preclinical model selection. Mol Cancer Res 12:571-82|
|Nakajima, Erica C; Laymon, Charles; Oborski, Matthew et al. (2014) Quantifying metabolic heterogeneity in head and neck tumors in real time: 2-DG uptake is highest in hypoxic tumor regions. PLoS One 9:e102452|
|Sen, Malabika; Paul, Kathleen; Freilino, Maria L et al. (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46-56|
|Stabile, Laura P; He, Guoqing; Lui, Vivian Wai Yan et al. (2013) c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met. Clin Cancer Res 19:380-92|
|Wheeler, Sarah; Siwak, Doris R; Chai, Raymond et al. (2012) Tumor epidermal growth factor receptor and EGFR PY1068 are independent prognostic indicators for head and neck squamous cell carcinoma. Clin Cancer Res 18:2278-89|
|Egloff, Ann Marie; Grandis, Jennifer R (2011) Response to combined molecular targeting: defining the role of P-STAT3. Clin Cancer Res 17:393-5|
|Sahu, Nivedita; Grandis, Jennifer Rubin (2011) New advances in molecular approaches to head and neck squamous cell carcinoma. Anticancer Drugs 22:656-64|
|Leeman-Neill, Rebecca J; Seethala, Raja R; Singh, Shivendra V et al. (2011) Inhibition of EGFR-STAT3 signaling with erlotinib prevents carcinogenesis in a chemically-induced mouse model of oral squamous cell carcinoma. Cancer Prev Res (Phila) 4:230-7|
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