Abstract 1985: Tbk1 loss in pancreatic cancer leads to changes in epithelial plasticity

Abstract

Abstract Effective therapies are needed to enhance the long-term survival of patients with pancreatic ductal adenocarcinoma (PDA), which is the fourth leading cause of cancer-related deaths in the United States and eighth worldwide. Initial stages of PDA are commonly characterized by an activating mutation in K-RAS, yet direct inhibition of K-RAS through pharmacological means remains a challenge. Higher levels of TANK Binding Kinase 1 (TBK1) mRNA, a critical downstream effector of mutant active K-RAS in lung cancer, are associated with poorer overall survival in a cohort of human PDA patients. We hypothesize that TBK1 is also an effective mediator of K-RAS driven pancreatic cancer. Here we report that TBK1 is expressed and more active in human PDA cell lines relative to immortalized pancreatic epithelial lines (HPNE) and fibroblasts. We found that human PDA cell lines are sensitive to a small molecule inhibitor of TBK1 in the low micromolar range. Further mice engineered to express a mutant kinase dead form of TBK1 (Tbk1Δ/Δ) are viable and fertile yet display smaller tumors at early time points in a genetically engineered mouse model of PDA. Interestingly, tumors from Tbk1Δ/Δ: PDA mice are more epithelial in gene expression and show significantly less collagen deposition compared to Tbk1+/+: PDA tumors. Additionally, cell lines isolated from Tbk1Δ/Δ: PDA tumors are more epithelial in morphology and less migratory and invasive relative to Tbk1+/+: PDA cell lines. Current work is focused on delineating the functional contribution of TBK1 to tumor cell motility in vivo as well as mechanistic understanding of the epithelial phenotype in Tbk1Δ/Δ: PDA tumors. These results will further our understanding of Ras signaling in pancreatic cancer and are critical for exploring a new avenue of targeted therapy. Citation Format: Victoria Haley Burton, Rolf A. Brekken, Melissa Gross, Alberto Bremauntz. Tbk1 loss in pancreatic cancer leads to changes in epithelial plasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1985. doi:10.1158/1538-7445.AM2017-1985