The protein kinase C family of serine/threonine kinases has been implicated in many forms of cancer, including lung cancer. Recent studies have demonstrated that PKC iota is important in cellular transformation by oncogenic Ras, the most commonly mutated oncogene in lung cancer. One goal of the present study is to examine the role PKC iota plays in oncogenic K-Ras-mediated lung carcinogenesis in vivo. Bitransgenic mice in which PKC iota signaling can be conditionally disrupted in the lung epithelium will be crossed to an established transgenic K-Ras mouse model of spontaneous K-Ras-mediated lung carcinogenesis. These mice will be used to assess the role of PKC iota signaling in the establishment and maintenance of K-Ras-mediated lung adenocarcinomas. Furthermore, preliminary data demonstrate that PKC iota is highly expressed in human non-small cell lung cancer (NSCLC) cell lines and primary NSCLC tumors, and that PKC iota gene amplification regulates PKC iota gene expression in a significant subset of these tumors. Cancer genes that are amplified in a subset of a particular type of tumor are often found to harbor somatic mutations in tumors in which the gene is not amplified. Based on these considerations, the proposed research will test the hypothesis that the PKC iota gene is a target of somatic mutation(s) in a subset of NSCLC tumors that do not exhibit PKC iota gene amplification. Genomic DNA from primary NSCLC that do not harbor PKC iota gene amplification along with patient-matched normal tissue will be sequenced and analyzed for somatic mutations at all 18 exons and the promoter region of the PKC iota gene. The proposed research will provide additional evidence validating PKC iota as an attractive prognostic and therapeutic tool for the detection and treatment of NSCLC.
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