Pancreatic Ductal Adenocarcinoma (PDA) is a devastating disease, with a 5-year survival of less than 6%. This survival rate has not changed in the last 60 years, due in large part to a lack of understanding of the molecular mechanisms underlying disease. Characterizing these aspects of PDA pathogenesis is necessary to develop more effective treatments and better outcomes for patients. Protein kinases are a therapeutic target and multiple small molecule inhibitors targeting them are being developed clinically. Recently, TANK-Binding Kinase-1 (TBK-1) has been associated with pancreatic cancer in humans. However, our functional understanding of the role of this kinase in pancreatic cancer is limited. In normal physiology TBK-1 is a pro-inflammatory mediator of interferon response as well as non-canonical NF-?B signaling and is primarily expressed in inflammatory cells. TBK-1 expression is dysregulated and overexpressed in many epithelial malignancies, including lung, breast, colon, and pancreatic cancers. Preliminary experiments revealed that PDA cells express TBK-1, and furthermore, inhibition of TBK-1 in PDA cells lead to abrogated cell growth in a 3D culture system. The mechanisms underpinning the requirement for TBK-1 in PDA three-dimensional growth are unknown. PDA TBK-1 inhibition in vitro also leads to decreased activity of AKT signaling and upregulation of pro-apoptotic gene expression, suggesting a possible mechanism of action. In biochemical assays, AKT acts as a direct target of TBK-1 activity; however, whether TBK-1 mediates PDA cell survival via AKT activation has yet to be directly tested. Using pharmacologic and genetic techniques, the proposed experiments will address the downstream mechanism of TBK-1 mediated PDA growth and the cellular mechanism of PDA growth abrogation upon TBK-1 inhibition. The protein kinase TBK-1 is expressed in a number of human malignancies, but its role in pancreatic cancer has not been fully characterized. There is an increasing interest in the role of TBK-1 in cancer biology, since TBK-1 can regulate many downstream pathways in cancer, including AKT. Many recent studies have established AKT as required for pancreatic cancer maintenance, thus it a potential therapeutic target. However, efforts to target AKT in humans have been complicated by severe adverse side effects of AKT inhibition. Those include severe skin rash and gastrointestinal distress, and are associated with tissues that depend on AKT for normal physiologic function. If AKT function is dependent upon TBK-1 activity in the context of pancreatic cancer, targeting TBK-1 may result in a wider therapeutic window, as TBK-1's role in normal physiology is limited to host defense rather than tissue maintenance.
The proposed project seeks to characterize the function of a gene (TBK-1) and the therapeutic potential of targeting it in the context of pancreatic cancer, the 4th leading cause of malignancy-related death. Thus, the focus of this work is in accordance with the NIH's mission to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.