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

Victoria H Cruz1, Emily N Arner1, Wenting Du1

  • 1Division of Surgical Oncology, Department of Surgery, and the Hamon Center for Therapeutic Oncology Research.

JCI Insight
|April 3, 2019
PubMed

Insights

Targeting TANK-binding kinase 1 (TBK1) may treat pancreatic ductal adenocarcinoma (PDA). TBK1 drives tumor growth and metastasis in KRAS-mutant PDA by promoting epithelial plasticity and invasion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Pancreatic ductal adenocarcinoma (PDA) is driven by KRAS mutations.
  • Directly inhibiting KRAS is challenging, necessitating alternative therapeutic strategies.
  • Identifying key KRAS effectors is crucial for developing novel PDA treatments.

Purpose of the Study:

  • To investigate the role of TANK-binding kinase 1 (TBK1) in KRAS-mutant PDA progression.
  • To elucidate the mechanisms by which TBK1 contributes to tumor growth and metastasis.
  • To explore the relationship between Axl receptor tyrosine kinase and TBK1 activity in PDA.

Main Methods:

  • Investigated the contribution of TBK1 to PDA progression in KRAS-mutant models.
  • Analyzed TBK1's role in driving epithelial plasticity, invasion, and metastasis.
  • Examined the induction of TBK1 activity by Axl receptor tyrosine kinase via Ras-RalB signaling.

Main Results:

  • TBK1 supports the growth and metastasis of KRAS-mutant PDA.
  • TBK1 drives an epithelial plasticity program that enhances tumor cell invasiveness.
  • Axl receptor tyrosine kinase induces TBK1 activity in a Ras-RalB-dependent manner.

Conclusions:

  • TBK1 is a critical downstream effector of mutant KRAS in PDA.
  • TBK1 is central to an Axl-driven epithelial-mesenchymal transition in KRAS-mutant PDA.
  • Targeting the Axl-TBK1 signaling cascade offers potential therapeutic strategies for PDA.
Keywords:
CancerOncology

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