Histopathologically similar neoplasms often represent diverse disease processes driven by distinct oncogenic events and pathways. Recognition of such differences in driving pathways between tumors is clearly the key to improving the success rate of therapies targeting these pathways. Epidermal growth factor receptor (EGFR) expression has prognostic significance in patients with head and neck squamous cell carcinoma (HNSCC) and antibodies targeting this receptor have been demonstrated in the clinic to be active in a subset of HNSCC patients. EGFR is overexpressed in over 95% of HNSCC and recently a truncation mutation, EGFR variant III (EGFRvlll), was found in 42% of HNSCC. EGFRvlll is always found with the wild-type receptor in co-expression, perhaps reflecting heterogeneity in individual cells or within clones of cells within a tumor. This heterogeneity may underlie clinically important mechanisms of resistance to targeted cancer treatment. Because EGFRvlll is constitutively activated independent of ligand-binding, it is postulated to be a mechanism of resistance to cetuximab, which inhibits EGFR activation by blocking ligand binding. Based on these data, we hypothesize that; 1) EGFRvlll is oncogenic and associated with cetuximab resistance in HNSCC, 2) the presence of an activated EGFR gene expression signature will allow us to select HNSCC patients with an increased likelihood of response to EGFR inhibitors.
Our first Aim i s to determine the activated EGFR signature in a genetically well defined model system of HaCaT cells overexpressing EGFR and to characterize the oncogenic properties of EGFRvlll in HaCaT cells. We will also examine gene expression differences regulated by ligand-dependent or ligand-independent activation of EGFR in this model system.
The second Aim i s to determine the activated EGFR signature in HNSCC cell lines to test and refine the signature as a biomarker of clinical response to EGFR inhibitors. We will also determine novel genes/pathways that are co-regulated with activation and inhibition of EGFR pathways to identify the off-target effect of cetuximab, mechanism of resistance and generate a rationale for combination therapy with current EGFR inhibitors.
Our third aim i s to determine presence of the activated EGFR signature generated from HaCaT cells and HNSCC cell lines and the EGFRvlll mutation as biomarkers of clinical response in HNSCC patients treated with cetuximab monotherapy. Ultimately, we expect that the findings from this study will be translated into improved patient selection and optimized treatment benefits from EGFR inhibitors in HNSCC patients.
|Ozawa, Hiroyuki; Ranaweera, Ruchira S; Izumchenko, Evgeny et al. (2017) SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells. Clin Cancer Res 23:5162-5175|
|Fertig, Elana J; Ozawa, Hiroyuki; Thakar, Manjusha et al. (2016) CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network. Oncotarget 7:73845-73864|
|Cheng, Haixia; Fertig, Elana J; Ozawa, Hiroyuki et al. (2015) Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma. Cancer Biol Ther 16:1252-8|
|Parker, Hilary S; Leek, Jeffrey T; Favorov, Alexander V et al. (2014) Preserving biological heterogeneity with a permuted surrogate variable analysis for genomics batch correction. Bioinformatics 30:2757-63|
|Chung, C H; Lee, J W; Slebos, R J et al. (2014) A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 25:2230-6|
|Bauman, Julie E; Arias-Pulido, Hugo; Lee, Sang-Joon et al. (2013) A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma. Oral Oncol 49:461-7|
|Fertig, Elana J; Ren, Qing; Cheng, Haixia et al. (2012) Gene expression signatures modulated by epidermal growth factor receptor activation and their relationship to cetuximab resistance in head and neck squamous cell carcinoma. BMC Genomics 13:160|
|Husain, Hatim; Psyrri, Amanda; Markovic, Ana et al. (2012) Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma. Laryngoscope 122:2762-8|
|Bedi, Atul; Chang, Xiaofei; Noonan, Kimberly et al. (2012) Inhibition of TGF-? enhances the in vivo antitumor efficacy of EGF receptor-targeted therapy. Mol Cancer Ther 11:2429-39|
|Wang, Jianbo; Zhang, Kaihua; Grabowska, Dorota et al. (2011) Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma. Mol Cancer Res 9:1686-95|
Showing the most recent 10 out of 24 publications