Abstract A71: Investigating the functional contribution of TANK Binding Kinase 1 to metabolic regulation in pancreas cancer

Abstract

Abstract Effective therapies are needed to enhance the long-term survival of patients with pancreatic ductal adenocarcinoma (PDA), the fourth leading cause of cancer-related deaths in the United States. Initial stages of human PDA are commonly characterized by an activating mutation in K-RAS along with extensive immune cell infiltration. Yet, effectively inhibiting K-RAS through pharmacological means has proven difficult. However, high levels of active TANK Binding Kinase 1 (TBK1), a critical downstream effector of mutant active K-RAS in lung cancer, are associated with inflammatory disease. TBK1 and homolog, IKKe can both activate the immune response transcription factor NF-κB. Interestingly, IKKe has been shown to regulate lipid and glucose metabolism by sustaining a state of chronic, low-grade inflammation in obese mice. Interestingly, IKKe has been shown to regulate energy balance by sustaining a state of chronic, low-grade inflammation in obese mice. Given this recent finding, we suspect that TBK1 can also promote glucose and lipid metabolism concerted with inflammation to promote pancreatic tumorigenensis. Therefore, we set out to distinguish TBK1 metabolic function and then determine if and how these TBK1 functions contribute to PDA. Homozygous Tbk1 deletion in a C57BL/6 genetic background is embryonic lethal (E14.5) due to massive liver degeneration and apoptosis. However, conditional deletion of the Tbk1 catalytic domain in the 129S5 mouse strain resulted in viable animals that express low levels of a truncated, enzymatically inactive form of TBK1. Various metabolic phenotyping experiments were performed with these Tbk1Δ/Δ mice to gain insight into the non-redundant metabolic roles of TBK1. In general we've observed that Tbk1Δ/Δ mice are significantly smaller, leaner and have less fat than Tbk1 +/+ mice on both normal chow and high fat chow. Accordingly, Tbk1Δ/Δ mice are more active and have increased thermogenesis relative to Tbk1 +/+ mice. In the PDA setting, TBK1 is expressed and more active in human PDA cell lines relative to immortalized pancreatic epithelial lines (HPNE) and fibroblasts. Human PDA cell lines are sensitive to a small molecule inhibition of TBK1 in the low micromolar range. TBK1 supports the growth of spontaneous pancreatic tumors in a K-Ras driven genetic mouse model of PDA, as evidenced by smaller tumors from Tbk1Δ/Δ: PDA mice relative to Tbk1 +/+: PDA mice at multiple timepoints. So far, our results imply that TBK1 contributes to metabolic regulation and demonstrate the therapeutic potential of targeting TBK1 in pancreatic malignancies. Current work is focused on delineating the inflammatory and metabolic dysregulation in these animals and determining the precise mechanism by which TBK1 supports pancreatic cancer. Citation Format: Victoria H. Burton, Rolf A. Brekken. Investigating the functional contribution of TANK Binding Kinase 1 to metabolic regulation in pancreas cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A71.