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

Victoria H. Cruz, Emily N. Arner, Wenting Du, Alberto E. Bremauntz, Rolf A Brekken

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere126117
JournalJCI Insight
Volume4
Issue number9
DOIs
StatePublished - Jan 1 2019

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Pancreatic Neoplasms
Phosphotransferases
Adenocarcinoma
Epithelial-Mesenchymal Transition
Pharmacology
Neoplasm Metastasis
Mutation
Therapeutics
Growth
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. / Cruz, Victoria H.; Arner, Emily N.; Du, Wenting; Bremauntz, Alberto E.; Brekken, Rolf A.

In: JCI Insight, Vol. 4, No. 9, e126117, 01.01.2019.

Research output: Contribution to journalArticle

Cruz, Victoria H. ; Arner, Emily N. ; Du, Wenting ; Bremauntz, Alberto E. ; Brekken, Rolf A. / Axl-mediated activation of TBK1 drives epithelial plasticity in pancreatic cancer. In: JCI Insight. 2019 ; Vol. 4, No. 9.
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