~10% of non-small cell lung cancer patients respond dramatically to Gefitinib (Iressa), a selective inhibitor of epidermal growth factor receptor (EGFR), and the presence of somatic EGFR mutations in tumors accurately predicts a clinical response. Mutant EGFRs exhibit a qualitative alteration of EGF-induced signaling suggesting that distinct signaling by mutant EGFRs contributes to drug-responsiveness in some lung tumors. Here, the oncogenic mechanism of these EGFR mutations and the mechanism underlying gefitinib-sensitivity will be established. The molecular basis for drug-response seen in a small subset of patients with tumors lacking EGFR mutations will also be examined.
Four Specific Aims are proposed: 1: To establish the biochemical mechanism by which EGFR mutants contribute to lung tumors. This will involve elucidating biochemical distinctions of mutant EGFRs through in vitro enzyme studies with purified kinase and synthetic peptide substrates. Enzyme activity, substrate specificity, and signaling complexes will be compared for wild-type and several tumor-derived EGFR mutants. A cell culture assay will be used to link the altered signaling properties of mutant EGFRs to distinct biological responses to EGF. 2: To determine the basis for drug-sensitivity and EGFR-dependence in tumors harboring EGFR mutants. Enzyme and cellular assays will be used to compare drug effects on wild-type and mutant EGFRs. The """"""""oncogene addiction"""""""" hypothesis will be examined in a cell culture model of signaling by mutant EGFRs. 3: To examine the role of other ErbB receptors in the oncogenic function and drug sensitivity of mutant EGFR. The hypothesis will be tested that heterodimers of mutant EGFR and another ErbB receptor contribute to the oncogenic actions of mutant EGFR and/or drug sensitivity. 4: To determine the molecular basis for gefitinib-response in the absence of EGFR mutations. A search for mutations in candidate genes in drug responsive tumors lacking EGFR mutations will be conducted. To establish a cell-based setting to study the response mechanism, lung cancer cell lines will be screened to identify drug-sensitive lines lacking EGFR mutations. Finally, microarray-based gene expression profiling will be used to identify a gene expression signature that defines drug-responsiveness. Together, these studies are expected to provide important insights into the molecular mechanisms that underlie the oncogenic activity of this novel class of EGFR mutants and the drug hypersensitivity exhibited by tumors that harbor these mutations.
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