Abstract A04: TBK1 as a novel mediator of K-Ras driven pancreatic cancer

Abstract

Abstract Effective therapies are needed to enhance the long-term survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related deaths in the United States and eighth worldwide. The mere 5-year survival rate of 5% is the lowest of all cancers and is due in part to late diagnosis and resistance to conventional therapy. Therefore, it is critical to identify molecular vulnerabilities in PDAC for developing targeted therapies. Activating point mutations in the small GTPase, K-Ras are present in 90% of PDAC cases. However, successful strategies that exploit the reliance of PDAC on mutant K-Ras have not been developed. Recent studies have shown that PDAC cell lines demonstrate a pronounced dependence on autophagy and that oncogenic Ras activates autophagy to maintain tumorigenesis. However, the mechanism by which oncogenic Ras induces autophagy is poorly understood. Notably, Tank Binding Kinase 1 (TBK1) operates downstream of the Ras effector, RalB to directly activate AKT pro-survival signaling, independent of mTOR and PI3K. In addition to supporting oncogenic transformation in cancer cells, TBK1 is a crucial component in antibacterial autophagy. This selective form of autophagy requires TBK1 to activate autophagic cargo receptors, p62 and Optineurin for enhanced autophagic clearance. Furthermore, mouse embryonic fibroblasts (MEFs) harvested from mice expressing mutant TBK1 show a block in autophagy, implicating TBK1 as a mediator of non-selective autophagy in addition to xenophagy. Therefore, we hypothesize that TBK1 is the Ras effector driving autophagy in pancreatic cancers to support tumorigenic growth. We assessed the effect of pharmacological inhibition of TBK1 with a derivative of 6-aminopyrazolopyrimidine (Compound II) in human pancreatic cancer cell lines and in a pre-clinical model of PDAC. Inhibition of TBK1 with Compound II substantially reduced cell viability in cancer cells with diverse oncogenotypes. Initial studies in a genetic mouse model of PDAC (p48-Cre; LSL-KrasG12D; Cdkn2alox/lox, KIC) treated with Compound II, show a reduction in tumor burden. Moreover, Compound II reduced the activity of AKT in tumor tissues and decreased disease progression as determined by histology and immunohistochemistry for amylase, a marker of normal acinar tissue. Further studies will be performed to examine the relative level of active autophagy in animals treated with Compound II. Additionally, the contribution of TBK1 to the autophagic pathway and development and progression of PDAC is being assessed by crossing TBK1 mutant animals with KIC mice. 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 H. Burton, Yi-Hung Ou, Jason E. Toombs, Michael A. White, Rolf A. Brekken. TBK1 as a novel mediator of K-Ras driven pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A04. doi: 10.1158/1557-3125.RASONC14-A04