Abstract 903: The IKKα kinase is a potential therapeutic target in K-Ras-induced lung cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.903-903
• Main Authors: Basseres, Daniela S., Ebbs, Aaron, Cogswell, Patricia C., Levantini, Elena, Baldwin, Albert S.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-903

Lung cancer is the leading cause of cancer deaths in the world. In lung cancer, K-Ras oncogenic mutations are widespread, and compounds used to target the biological activity of the Ras proteins failed in clinical trials. Therefore, it is imperative to identify novel therapeutic targets that reduce K-Ras-induced lung tumorigenesis. We have previously shown that K-Ras-induced lung tumorigenesis is potentiated by the subunit p65 of the transcription factor NF-κB; and that K-Ras-induced NF-κB activation in the lung requires IKKα. Therefore, we hypothesized the following: (1) the IKKα kinase promotes K-Ras-induced oncogenesis; and (2) pharmacological inhibition of IKKα activity will be beneficial therapeutically. We used genetic and/or pharmacological approaches to inactivate IKKα in primary lung epithelial cells transformed by K-Ras, as well as K-Ras-positive lung cancer cell lines, and determined that IKKα inhibiton reduces oncogenic properties in vitro. In addition we used a highly specific IKKα inhibitor (CmpdA, Bayer) to treat a K-Ras-induced lung cancer mouse model combined with loss of the tumor suppressor p53 (LSL-K-RasG12D/p53fl/fl). We chose this model for the following reasons: (1) K-Ras activation coupled to p53 loss leads to aggressive lung adenocarcinomas in mice that better resemble human lung tumors; (2) lung cancer patients harboring K-Ras oncogenic mutations frequently display p53 inactivation; and (3) it has been recently demonstrated that p53 loss can enhance NF-κB activation by K-Ras in lung tumors. To induce concomitant K-Ras activation and p53 loss in murine lung epithelial cells, we infected the lungs of LSL-K-RasG12D/p53fl/fl mice by intranasal administration of a Cre-expressing adenovirus (AdCre). Two treatment regimens were used to treat infected animals: CmpdA was either administered daily for 2 weeks immediately following AdCre infection or daily for 4 weeks starting 8 weeks post-infection. In either case, mice treated with CmpdA presented smaller and lower grade tumors than mice treated with placebo. These results show that IKKα promotes lung cancer growth and progression both in vitro and in vivo. In addition, we have shown that pharmacological administration of an IKKα inhibitor slows lung tumor growth and progression in vivo, supporting our hypothesis that IKKα inhibition therapy will have clinical benefits in lung cancer. This research is supported by a FAMRI YCSA Award and a FAPESP Young Investigator Award to DB and a NIH gra