Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth
Thanh U. Barbie, … , David A. Barbie, William E. Gillanders
Thanh U. Barbie, … , David A. Barbie, William E. Gillanders
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5411-5423. https://doi.org/10.1172/JCI75661.
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Research Article Oncology

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

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Figure 6

CYT387 inhibits IKBKE signaling and tumor progression in vivo.

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CYT387 inhibits IKBKE signaling and tumor progression in vivo. (A) MDA-M...
(A) MDA-MB-468 cells were implanted subcutaneously in nude mice, and following the development of established xenograft tumors, vehicle or CYT387 100 mg/kg was administered daily by oral gavage. Levels of pSTAT3 were measured by immunohistochemistry following short-term treatment. HE, hematoxylin eosin stain. Scale bar: 25 μM. (B) Mean tumor volume ± SEM following vehicle (n = 4) or CYT387 (n = 5) treatment over time in MDA-MB-468 or MDA-MB-468 IKBKE-Y88C xenografts. (C) Mean tumor volume ± SEM following vehicle (n = 5) or CYT387 100 mg/kg/d (n = 5) treatment over 14 days in WHIM4 and WHIM21 primary human tumor xenografts. (D) Relative mRNA levels of human IKBKE, CCL5, and IL6 in WHIM21 tumors following short-term vehicle or CYT387 treatment. Values represent mean and SEM of triplicate samples from 2 different animals.