Requirement of the NF-κB Subunit p65/RelA for K-Ras-Induced Lung Tumorigenesis

K-Ras-induced lung cancer is a very common disease, for which there are currently no effective therapies. Because therapy directly targeting the activity of oncogenic Ras has been unsuccessful, a different approach for novel therapy design is to identify critical Ras downstream oncogenic targets. Given that oncogenic Ras proteins activate the transcription factor NF-kappa B, and the importance of NF-kappa B in oncogenesis, we hypothesized that NF-kappa B would be an important K-Ras target in lung cancer. To address this hypothesis, we generated a NF-kappa B-EGFP reporter mouse model of K-Ras-induced lung cancer and determined that K-Ras activates NF-kappa B in lung tumors in situ. Furthermore, a mouse model was generated where activation of oncogenic K-Ras in lung cells was coupled with inactivation of the NF-kappa B subunit p65/RelA. In this model, deletion of p65/RelA reduces the number of K-Ras-induced lung tumors both in the presence and in the absence of the tumor suppressor p53. Lung tumors with loss of p65/RelA have higher numbers of apoptotic cells, reduced spread, and lower grade. Using lung cell lines expressing oncogenic K-Ras, we show that NF-kappa B is activated in these cells in a K-Ras-dependent manner and that NF-kappa B activation by K-Ras requires inhibitor of kappa B kinase beta (IKK beta) kinase activity. Taken together, these results show the importance of the NF-kappa B subunit p65/RelA in K-Ras-induced lung transformation and identify IKK beta as a potential therapeutic target for K-Ras-induced lung cancer. Cancer Res; 70(9); 3537-46. (C) 2010 AACR.