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.
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