This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Background - Epidermal growth factor receptor (EGFR) over-expression is frequently observed in lung tumors and pre-cancerous lesion and induces tumor formation in animal studies. EGFR regulates important processes in carcinogenesis, including cell survival, cell-cycle progression, tumor invasion, and angiogenesis. Therapeutic efficacy with EGFR tyrosine kinase inhibitors (EGFR-TKI) that block EGFR activation is already being observed clinically in the recently FDA-approved treatment of non-small cell lung cancer (NSCLC). Yet, responsiveness to these drugs varies dramatically between patients, and reliable predictors have not been identified or validated. Despite the clinical importance of this pathway, those specific factors that cause alterations in EGFR remain largely unknown and there is evidence that they occur more frequently in non-smokers. -Hypothesis - As carcinogenic metals of concern, we hypothesize that arsenic and nickel exposure alter EGFR signaling and or promote mutations in the EGFR gene.-Approach - We propose to investigate the role of arsenic and nickel in EGFR pathway regulation in two experimental systems: 1) in cell culture using the BEAS-2B human lung epithelial cell lines, and 2) in tumor specimens obtained from early stage non-small cell lung cancer cases (enrolled in COBRE project 5).-Relevance - These studies will provide new mechanistic insights into specific environmental agents that promote lung carcinogenesis. Characterizing an exposure that impacts the EGFR signaling pathway will help optimize use of targeted screening and molecular diagnostics. We can then identify subsets of potentially responsive cases and who will benefit from pharmacologic EGFR inhibition as a therapeutic strategy in the lung.
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