Abstract A15: Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS, which is critical for the biology of PDA progression. Direct inhibition of KRAS through pharmacologic means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. Higher levels of TANK-binding kinase 1 (TBK1) mRNA, a critical downstream effector of mutant active KRAS, are associated with poorer overall survival in human PDA patients. We report that TBK1 supports the growth and metastasis of KRAS mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. Further, we identify that the receptor tyrosine kinase Axl induces TBK1 activity in a Ras-RalB-dependent manner. These findings demonstrate that TBK1 is central to Axl-driven EMT in KRAS mutant PDA and suggest that interruption of the Axl-TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease. Citation Format: Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A. Brekken. Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A15.