Wheeler, Sarah
(2012)
EGFRvIII expression and signaling in head and neck squamous cell carcinoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the United States and is even more prevalent in many developing countries. The mortality rate of ~50% has remained unchanged for decades emphasizing the need to increase our understanding of HNSCC biology. Overexpression of EGFR is found in up to 90% of HNSCC cases and has been implicated in oncogenicity by providing sustained signaling for cell proliferation, anti-apoptosis, angiogenesis and metastasis. Cetuximab (an EGFR specific monoclonal antibody) was FDA-approved for HNSCC in 2006 making it the first new HNSCC treatment in 45 years. However, the clinical response to cetuximab is only 10%, indicating the need to better understand the mechanisms of EGFR biology in HNSCC and investigate the mechanisms of tumor growth in the presence of wtEGFR blockade.
An altered form of EGFR, EGFRvIII, lacks exons 2-7 and is a probable mechanism of cetuximab resistance. We previously reported EGFRvIII to be expressed in ~40% of HNSCC tumors where HNSCC cells expressing EGFRvIII were relatively resistant to cetuximab treatment in xenograft models. The present study was undertaken to determine the prognostic significance of EGFR amplification, mRNA and protein levels in HNSCC and to better understand the biology of EGFRvIII in HNSCC.
We found that EGFR protein levels and phosphorylation status are the best indicators of patient prognosis. Utilizing the Cancer Genome Atlas data and clinical samples we found that EGFRvIII expression in GBM is often a DNA or transcriptional aberration but in HNSCC it is more likely a splice variant. We developed HNSCC cell lines expressing EGFRvIII and utilizing these models in vitro and in vivo, we were able to determine that EGFRvIII increases HNSCC invasion and migration via STAT3 and knockdown of STAT3 using siRNA or a transcriptional decoy abrogated invasion and migration. Akt was involved in EGFRvIII-mediated proliferation, but not invasion. SFKs were also found to be involved in EGFRvIII invasion and migration, specifically Lyn. In vivo xenograft growth was significantly inhibited by treatment with the SFK inhibitor dasatinib.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
8 February 2012 |
| Date Type: |
Publication |
| Defense Date: |
31 May 2011 |
| Approval Date: |
8 February 2012 |
| Submission Date: |
10 January 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
182 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
cancer, EGFR, Src, STAT3, EGFRvIII, head and neck cancer |
| Date Deposited: |
08 Feb 2012 17:36 |
| Last Modified: |
15 Nov 2016 13:55 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10891 |
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