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

JCI Insight. 2019 Apr 2;5(9):e126117. doi: 10.1172/jci.insight.126117.

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 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.

Keywords: Cancer; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, p16
  • Humans
  • Lung / pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Pancreas / pathology
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • Wound Healing
  • ral GTP-Binding Proteins / metabolism

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Ralb protein, human
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • Proto-Oncogene Proteins p21(ras)
  • ral GTP-Binding Proteins
  • Axl Receptor Tyrosine Kinase