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

Abstract

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.

• Authors: Thanh U Barbie, Gabriela Alexe, Amir R Aref, Shunqiang Li, Zehua Zhu, Xiuli Zhang, Yu Imamura, Tran C Thai, Ying Huang, Michaela Bowden, John Herndon, Travis J Cohoon, Timothy Fleming, Pablo Tamayo, Jill P Mesirov, Shuji Ogino, Kwok-Kin Wong, Matthew J Ellis, William C Hahn, David A Barbie, William E Gillanders
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 12 Pg. 5411-23 (Dec 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 25365225 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 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

Topics

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