Abstract A91: IKBKE signaling in pancreatic tumorigenesis

Abstract

Abstract Oncogenic activation of Kras is an important event in Pancreatic Ductal Adenocarcinoma (PDAC), that leads to activation of multiple signaling pathways. Although Kras is conceptually an attractive therapeutic target for PDAC, attempts made to target Kras using small molecules have been mostly unsuccessful. Another approach in treating pancreatic cancer is to target downstream effectors of Kras. We have previously shown that non-canonical activity of the Gli transcription factors downstream of Kras is required for the initiation and progression of pancreatic tumors, and that Gli drives a unique pancreas specific transcriptional program in the context of oncogenic Kras. Here, we demonstrate that the IkB Kinase Epsilon (IKBKE) is a novel transcriptional target of Gli that is essential for pancreatic transformation. Using genetically modified mouse models, we show that IKBKE activity, while dispensable for pancreatic development, is required for oncogenic transformation in the pancreas. We find that the genetic knockout of IKBKE leads to a dramatic inhibition of initiation and progression of pancreatic intraepithelial neoplasia (PanIN) precursor lesions in mice carrying pancreas specific activation of oncogenic Kras. Furthermore, we find that although IKBKE is a known NF-kB activator, it only modestly regulates NF-kB activity in PDAC. In contrast we find that IKBKE strongly promotes Akt phosphorylation in PDAC in vitro and in vivo, indicating that this may be the primary mechanism of IKBKE induced tumorigenesis. Our findings support the evaluation of IKBKE as a novel therapeutic target in treatment of pancreatic cancer. Citation Format: Mihir Rajurkar, Junhao Mao. IKBKE signaling in pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A91.