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JCI Insight. 2019 Apr 2;5. pii: 126117. doi: 10.1172/jci.insight.126117.

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer.

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Division of Surgical Oncology, Department of Surgery, and the Hamon Center for Therapeutic Oncology Research.
Department of Internal Medicine, and.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.


Pancreatic ductal adenocarcinoma (PDA) is characterized by an activating mutation in KRAS. Direct inhibition of KRAS through pharmacological means remains a challenge; however, targeting key KRAS effectors has therapeutic potential. We investigated the contribution of TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, to PDA progression. 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 an Axl-driven epithelial-mesenchymal transition 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.


Cancer; Oncology

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