Intracellular Signaling Mechanisms of Resistance to EGFR-Targeting Agents

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