Intracellular Signaling Mechanisms of Resistance to EGFR-Targeting AgentsQuesnelle, Kelly M. (2012) Intracellular Signaling Mechanisms of Resistance to EGFR-Targeting Agents. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractThe epidermal growth factor receptor (EGFR) is widely expressed in head and neck squamous cell carcinomas (HNSCC) and activates many growth and survival pathways within tumor cells. EGFR-targeting agents are only modestly effective in treating HNSCC, however, and a consistent mechanism of resistance has not been identified, in part, due to the paucity of preclinical models. This dissertation focuses on generating EGFR-inhibitor resistant preclinical models in order to identify biomarkers that may be predictive of response to these agents. We have assessed the response of a panel of HNSCC cell lines to the EGFR inhibitors erlotinib and cetuximab to determine their relevance as models of resistance to these agents. We defined a narrow range of response to erlotinib in HNSCC cells in vitro. We attempted to generate models of cetuximab resistance in cell line-derived xenografts and heterotopic tumorgrafts directly from primary HNSCC patient tumors. Our studies in HNSCC suggest that heterotopic xenografts are more representative of patient response to cetuximab than cell-line derived xenografts, although we did establish a model of cetuximab resistance from bladder cancer cell line-derived xenografts. A candidate-based approach was used to examine the role of HER2, HER3, and c-Met on mediating EGFR inhibitor resistance. We identified increased phosphorylation of a carboxyl-terminal fragment of HER2 (611-CTF) in cetuximab-resistant cells. Afatinib, an irreversible kinase inhibitor targeting EGFR and HER2, successfully restored cetuximab sensitivity in vitro. When afatinib was combined with cetuximab in vivo, we observed an additive growth inhibitory effect in cetuximab-resistant xenografts. We also show that while c-Met activity is not sufficient to alter cellular response to erlotinib, concomitant inhibition of c-Met and EGFR is required for the deactivation of MAPK in the presence of stimulatory ligands. These data support the proposed role for co-targeting c-Met with EGFR in the treatment of HNSCC. The studies presented here are significant because, in addition to suggesting that 611-CTF may be a novel biomarker for cetuximab resistance, they provide a thorough assessment of modeling EGFR inhibitor resistance in HNSCC and suggest heterotopic tumorgrafts as a plausible new model for examining cetuximab resistance in future studies. Share
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