Abstract 22: Investigating the functional contribution of TANK binding kinase 1 to inflammation induced disease progression
Authors: Burton Victoria H. , Brekken Rolf A. 
Published: July 2016

Initial stages of human pancreatic ductal adenocarcinoma (PDA) are commonly characterized by an activating mutation in K-RAS along with extensive immune cell infiltration. Direct inhibition of K-RAS through pharmacological means remains a challenge; however targeted inhibition of TANK Binding Kinase 1 (TBK1), a critical downstream effector of mutant active K-RAS is an attractive alternative. High levels of active TBK1 are associated with inflammatory disease and cancer progression. TBK1 and homolog, IKKe activate the immune response transcription factor NF-κB. In metabolically challenged mice, IKKe regulates energy balance by sustaining chronic, low-grade inflammation. We hypothesize that TBK1 signaling is also critical in metabolic regulation and is required for progression of inflammation-induced diseases such as PDA.

A kinase dead, Tbk1Δ/Δ mouse was used to determine the contribution of TBK1 to metabolic disease and PDA progression. Metabolic phenotyping experiments were performed with Tbk1Δ/Δ and Tbk1+/+ mice including a high fat diet weight study, body composition and metabolic chamber analyses. Tbk1+/+ and Tbk1Δ/Δ mice were crossed into a genetically engineered mouse model of PDA to determine the consequences of genetically removing Tbk1 on tumor development and overall survival.

Here we report that Tbk1Δ/Δ mice are significantly smaller, leaner and have less fat than Tbk1+/+ mice on high fat chow diets (HFD) for 14 weeks. Tbk1Δ/Δ mice are more active and have smaller and more abundant adipocytes relative to Tbk1+/+ mice. Additionally, Tbk1Δ/Δ mice are protected from HFD induced hypercholesterolemia and liver steatosis. White adipose tissue (WAT) from HFD fed Tbk1Δ/Δ mice exhibit an induction of brown fat gene expression suggesting that thermogenesis is a contributor to their healthier and more active phenotype. Macrophage infiltration is fairly low in WAT from Tbk1+/+ and Tbk1Δ/Δ mice on normal chow. However on HFD, WAT from Tbk1+/+ mice display a significant increase in macrophage marker expression compared to Tbk1Δ/Δ mice. These findings indicate that HFD fed Tbk1Δ/Δ mice are protected from classic phenotypes of metabolic syndrome.

In PDA, TBK1 is expressed and more active in human PDA cell lines relative to immortalized pancreatic epithelial lines and fibroblasts. Human PDA cell lines are sensitive to a small molecule inhibitor of TBK1 (compound II) in the low micromolar range. In a K-Ras driven genetic mouse model of PDA, TBK1 supports spontaneous pancreatic tumor growth as evidenced by smaller tumors in Tbk1Δ/Δ: PDA mice relative to Tbk1+/+: PDA mice. Our results suggest 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 the progression of PDA.

Citation Format: Victoria H. Burton, Rolf A. Brekken. Investigating the functional contribution of TANK binding kinase 1 to inflammation induced disease progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 22.