PKC iota is an oncogene in non-small cell lung cancer

描述(申请人提供)：丝氨酸/苏氨酸激酶的蛋白激酶C家族与多种形式的癌症有关，包括肺癌。最近的研究表明，PKC IOTA在肺癌中最常见的突变癌基因RAS的细胞转化中起重要作用。本研究的目的之一是研究PKC IOTA在体内K-RAS介导的致癌肺癌发生中所起的作用。在双基因小鼠中，肺上皮细胞中的PKC IOTA信号可以被有条件地中断，这将被交叉到一个已建立的K-RAS自发的K-RAS介导的肺癌的转基因小鼠模型中。这些小鼠将被用来评估PKC IOTA信号在K-RAS介导的肺腺癌的建立和维持中的作用。此外，初步数据表明，PKC IOTA在人非小细胞肺癌(NSCLC)细胞系和原发的NSCLC肿瘤中高表达，并且PKC IOTA基因扩增调节这些肿瘤中的一个重要亚群的PKC IOTA基因的表达。在特定类型的肿瘤的子集中扩增的癌症基因经常被发现在肿瘤中存在体细胞突变，而在这些肿瘤中该基因没有被扩增。基于这些考虑，拟议的研究将检验PKC IOTA基因是体细胞突变目标的假设(S)，在没有显示PKC IOTA基因扩增的非小细胞肺癌肿瘤的子集中。来自没有PKC IOTA基因扩增的原发NSCLC的基因组DNA将被测序，并分析所有18个外显子和PKC IOTA基因启动子区域的体细胞突变。这项拟议的研究将提供更多的证据，证实PKC IOTA是一种有吸引力的预后和治疗工具，用于检测和治疗NSCLC。

DESCRIPTION (provided by applicant): 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.