Three lines of investigation demonstrate that lung adenocarcinomaswith mutations in the EGFR or KRASproto-oncogenes are dependent on continued function of the oncogenes: (1) human tumors regress inresponse to EGFR inhibitors, (2) lung adenocarcinomasin mouse models disappear when mutantoncogenes are down-regulated or inhibited by drugs, and (3) cell lines derived from human lungadenocarcinomas are sensitive to allele-specific inhibitory RNAs and EGFR inhibitors. These findingssuggest that it may be possible to develop more effective means to treat adenocarcinoma of the lung by;learning more about essential components of signaling pathwaysdriven by mutant EGFR or KRAS. Toapproach this possibility, we will use well-characterized human cell lines, transgenic mice, chemical libraries,and new protein chemistry methods to identify such components. Specifically, we will use a highthroughput, cell-based screen of lung adenocarcinoma cell lines against small molecule libraries to identifythe molecular targets of a few compounds that have strong growth-inhibitory or cell death-inducing activity.In addition, we will identify proteins that are affiliated with or phosphorylated by mutant EGFRs in human celllines or transgenic mouse tumors. Selected proteins will be studied further by manipulating and analyzingtheir expression in cell lines and transgenic mice.
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