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

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Abstract

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 KRASmutant PDA and suggest that interruption of the Axl/TBK1 signaling cascade above or below KRAS has potential therapeutic efficacy in this recalcitrant disease.

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Cruz, V. H., Arner, E. N., Du, W., Bremauntz, A. E., & Brekken, R. A. (2019). Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. JCI Insight, 4(9). https://doi.org/10.1172/jci.insight.126117

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