Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth

J Clin Invest. 2014 Dec;124(12):5411-23. doi: 10.1172/JCI75661. Epub 2014 Nov 3.


Triple-negative breast cancers (TNBCs) are a heterogeneous set of cancers that are defined by the absence of hormone receptor expression and HER2 amplification. Here, we found that inducible IκB kinase-related (IKK-related) kinase IKBKE expression and JAK/STAT pathway activation compose a cytokine signaling network in the immune-activated subset of TNBC. We found that treatment of cultured IKBKE-driven breast cancer cells with CYT387, a potent inhibitor of TBK1/IKBKE and JAK signaling, impairs proliferation, while inhibition of JAK alone does not. CYT387 treatment inhibited activation of both NF-κB and STAT and disrupted expression of the protumorigenic cytokines CCL5 and IL-6 in these IKBKE-driven breast cancer cells. Moreover, in 3D culture models, the addition of CCL5 and IL-6 to the media not only promoted tumor spheroid dispersal but also stimulated proliferation and migration of endothelial cells. Interruption of cytokine signaling by CYT387 in vivo impaired the growth of an IKBKE-driven TNBC cell line and patient-derived xenografts (PDXs). A combination of CYT387 therapy with a MEK inhibitor was particularly effective, abrogating tumor growth and angiogenesis in an aggressive PDX model of TNBC. Together, these findings reveal that IKBKE-associated cytokine signaling promotes tumorigenicity of immune-driven TNBC and identify a potential therapeutic strategy using clinically available compounds.

Publication types

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

MeSH terms

  • Animals
  • Benzamides / pharmacology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Chemokine CCL5 / genetics
  • Chemokine CCL5 / metabolism*
  • Female
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Pyrimidines / pharmacology
  • Signal Transduction*
  • Xenograft Model Antitumor Assays


  • Benzamides
  • CCL5 protein, human
  • Chemokine CCL5
  • IL6 protein, human
  • Interleukin-6
  • NF-kappa B
  • Neoplasm Proteins
  • Pyrimidines
  • N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide
  • Janus Kinases
  • I-kappa B Kinase
  • IKBKE protein, human