Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit

Cancer Discov. 2014 Apr;4(4):452-65. doi: 10.1158/2159-8290.CD-13-0646. Epub 2014 Jan 20.

Abstract

Although the roles of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling in KRAS-driven tumorigenesis are well established, KRAS activates additional pathways required for tumor maintenance, the inhibition of which are likely to be necessary for effective KRAS-directed therapy. Here, we show that the IκB kinase (IKK)-related kinases Tank-binding kinase-1 (TBK1) and IKKε promote KRAS-driven tumorigenesis by regulating autocrine CCL5 and interleukin (IL)-6 and identify CYT387 as a potent JAK/TBK1/IKKε inhibitor. CYT387 treatment ablates RAS-associated cytokine signaling and impairs Kras-driven murine lung cancer growth. Combined CYT387 treatment and MAPK pathway inhibition induces regression of aggressive murine lung adenocarcinomas driven by Kras mutation and p53 loss. These observations reveal that TBK1/IKKε promote tumor survival by activating CCL5 and IL-6 and identify concurrent inhibition of TBK1/IKKε, Janus-activated kinase (JAK), and MEK signaling as an effective approach to inhibit the actions of oncogenic KRAS.

Publication types

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

MeSH terms

  • Animals
  • Autocrine Communication*
  • Benzamides / pharmacology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Line, Tumor
  • Chemokine CCL5 / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • I-kappa B Proteins / metabolism
  • Interleukin-6 / metabolism
  • Mice
  • Neoplasms, Experimental
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidines / pharmacology*
  • Signal Transduction / drug effects*
  • ras Proteins / genetics*

Substances

  • Benzamides
  • Chemokine CCL5
  • I-kappa B Proteins
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Pyrimidines
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • Protein-Serine-Threonine Kinases
  • ras Proteins