Mutant EGF Receptor-Dependent Lung Cancer in Human Cell Lines and Transgenic Mice

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DESCRIPTION (provided by applicant): FOA: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications PARENT GRANT: 5 R01 CA120247-03 The adenocarcinoma subtype of non-small cell lung cancer (NSCLC) appears to be rising in incidence and now comprises approximately 40 percent of all cases of lung cancer. Somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of lung adenocarcinomas, and these mutations are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Although the initial clinical response is often dramatic, virtually all patients will eventually develop resistance to these drugs. To enhance our understanding of tumorigenesis and resistance to EGFR TKIs, our laboratory has established a mouse model of lung adenocarcinoma by generating mice with tetracycline- inducible mutant human EGFR transgenes expressed in lung epithelium. These mice develop lung adenocarcinomas on doxycycline that rapidly regress in response to withdrawal of doxycycline or treatment with erlotinib. We are now using this model as well as human lung adenocarcinoma cell lines that harbor EGFR mutations to identify genetic lesions that can cooperate with mutant EGFRs in tumorigenesis or confer resistance to EGFR TKIs. We will screen for these genetic alterations by inducing Sleeping Beauty (SB) transposon-tagged insertional mutagenesis in vivo in mouse lung and in vitro in cell lines. Through characterization of the mutations isolated in these screens we seek to identify novel genetic lesions that contribute to the pathogenesis or response to treatment of human mutant EGFR-driven lung adenocarcinomas. PUBLIC HEALTH RELEVANCE: We propose to broaden our studies of mouse models of human lung cancer to include work with a transposable element, called Sleeping Beauty (SB), that will permit us to look for mutations that accelerate EGFR-initiated tumorigenesis or promote resistance to drug therapy, issues that are directly relevant to the treatment of human lung cancers. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page