Requirement of the NF-kB 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-?B, and the importance of NF-?B in oncogenesis, we hypothesized that NF-?B would be an important K-Ras target in lung cancer. To address this hypothesis, we generated a NF-?B-EGFP reporter mouse model of K-Ras-induced lung cancer and determined that K-Ras activates NF-?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-?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-?B is activated in these cells in a K-Ras-dependent manner and that NF-?B activation by K-Ras requires inhibitor of ?B kinase ? (IKK?) kinase activity. Taken together, these results show the importance of the NF-?B subunit p65/RelA in K-Ras-induced lung transformation and identify IKK? as a potential therapeutic target for K-Ras-induced lung cancer.