Targeting EGFR and KRAS Mutations

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Three lines of investigation demonstrate that lung adenocarcinomaswith mutations in the EGFR or KRAS proto-oncogenes are dependent on continued function of the oncogenes: (1) human tumors regress in response to EGFR inhibitors, (2) lung adenocarcinomasin mouse models disappear when mutant oncogenes are down-regulated or inhibited by drugs, and (3) cell lines derived from human lung adenocarcinomas are sensitive to allele-specific inhibitory RNAs and EGFR inhibitors. These findings suggest 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. To approach 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 high throughput, cell-based screen of lung adenocarcinoma cell lines against small molecule libraries to identify the 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 cell lines or transgenic mouse tumors. Selected proteins will be studied further by manipulating and analyzing their expression in cell lines and transgenic mice.