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

描述（由申请人提供）：丝氨酸/苏氨酸激酶的蛋白激酶C家族与许多形式的癌症有关，包括肺癌。最近的研究表明，PKC iota在致癌Ras（肺癌中最常见的突变癌基因）的细胞转化中是重要的。本研究的目的之一是研究PKC iota在体内致癌K-Ras介导的肺癌发生中的作用。将其中肺上皮中的PKC iota信号传导可以被条件性破坏的双转基因小鼠与自发K-Ras介导的肺癌发生的已建立的转基因K-Ras小鼠模型杂交。这些小鼠将用于评估PKC iota信号传导在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）细胞系和原发性NSCLC肿瘤中高度表达，并且PKC iota基因扩增调节这些肿瘤的重要子集中的PKC iota基因表达。在特定类型的肿瘤的子集中扩增的癌症基因通常被发现在基因未扩增的肿瘤中具有体细胞突变。基于这些考虑，拟议的研究将检验以下假设：PKC iota基因是未表现出PKC iota基因扩增的NSCLC肿瘤亚组中体细胞突变的靶点。将对未携带PKC iota基因扩增的原发性NSCLC的基因组DNA沿着患者匹配的正常组织进行测序，并分析PKC iota基因的所有18个外显子和启动子区的体细胞突变。拟议的研究将提供额外的证据，验证PKC iota作为检测和治疗NSCLC的有吸引力的预后和治疗工具。

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.