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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies lacking effective therapeutic strategies. Here, we show that the noncanonical IκB-related kinase, IKBKE, is a critical oncogenic effector during KRAS-induced pancreatic transformation. Loss of IKBKE inhibits the initiation and progression of pancreatic tumors in mice carrying pancreatic-specific KRAS activation. Mechanistically, we demonstrate that this protumoral effect of IKBKE involves the activation of GLI1 and AKT signaling and is independent of the levels of activity of the NF-κB pathway. Further analysis reveals that IKBKE regulates GLI1 nuclear translocation and promotes the reactivation of AKT post-inhibition of mTOR in PDAC cells. Interestingly, combined inhibition of IKBKE and mTOR synergistically blocks pancreatic tumor growth. Together, our findings highlight the functional importance of IKBKE in pancreatic cancer, support the evaluation of IKBKE as a therapeutic target in PDAC, and suggest IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Cancer Res; 77(2); 320–9. ©2017 AACR.

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.

Serrated polyps have recently been proposed to comprise at least 30% of the origins of human colorectal cancer (CRC). Unlike adenomatous polyps, which are initiated by APC/β-catenin mutations, the genetic and molecular mechanisms underlying the serrated pathway that leads to serrated polyp initiation and progression remain poorly understood. Here we describe a novel genetically modified mouse model of serrated polyposis via conditional activation of SMAD7, an inhibitory SMAD protein, in the intestinal epithelia. We show that SMAD7 activation is sufficient to drive serrated polyp initiation and progression to aggressive adenocarcinoma in both mouse intestine and colon. Mechanistically, we find that SMAD7-induced foci formation in non-transformed intestinal epithelial cells in vitro and serrated polyposis in vivo are Wnt/β-catenin independent. Furthermore, we find that, in addition to its regulation of TGFβ/BMP pathway, SMAD7 interacts with BRAF/MAPK signaling to regulate serrated polyposis. Taken together, our studies implicate for the first time the involvement of SMAD7 in serrated polyposis and reveal a potential novel molecular mechanism underlying the serrated polyp pathway. Citation Format: Jennifer Cotton, He Huang, Mihir Rajurkar, Junhao Mao. A novel mouse model for intestinal serrated polyposis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2014-98

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