Abstract LB-105: Gli-IKBKE interactions in pancreatic tumorigenesis

Abstract

Abstract Oncogenic mutations in KRAS are detected in a majority of human pancreatic malignancies, and are considered an initiating event in pancreatic ductal adenocarcinoma (PDAC). The downstream mechanisms through which KRAS drives tumorigenesis remain elusive. While recent in vitro studies have suggested that Gli proteins, the transcriptional effectors of Hedgehog signaling, may mediate KRAS oncogenic activity in PDAC cell lines, a requirement for Gli activation in pancreatic tumorigenesis has not been demonstrated in vivo. Here, we use genetically modified mouse models, and human PDAC cell lines to establish a requirement for Gli activation in KRAS initiation of pancreatic tumorigenesis, and identify IKBKE as a novel oncogenic target gene of Gli in PDAC. We show for the first time that inhibition of Gli transcription in the pancreatic epithelium suppressed the ability of activated KRAS to initiate tumorigenesis in vivo. Also, we find that expression of Gli1 along with oncogenic KRAS led to a dramatic acceleration in the formation of pancreatic intraepithelial neoplasia (PanIN) lesions, and increased mortality. Importantly, we identify IKBKE as a novel transcriptional target of Gli in PDAC cells, and also in the pancreatic epithelium in vivo. We also demonstrate that IKBKE is required for the survival and tumorigenicity of PDAC cells, thus implicating IKBKE as a novel pancreatic cancer oncogene. We have found that IKBKE activates the NF-kB pathway, and also activates Akt by phosphorylation in PDAC cells as part of its tumorigenic activity. Our studies demonstrate for the first time a requirement for Gli transcriptional activity in KRAS induced pancreatic tumorigenesis in vivo, and establish IKBKE as a novel Gli target and pancreatic cancer oncogene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-105. doi:1538-7445.AM2012-LB-105