Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 12, Pages 5411-5423Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI75661
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Funding
- NIH [T32 CA009621, P01 CA154303, R01 CA130988, K08 CA13891801A1]
- US Department of Defense Breast Cancer Award [W81XWH-13-1-0029]
- V Scholar, Gloria Spivak Faculty, GTM Fund for Lung Cancer Research, and Friends of the Dana-Farber Cancer Institute Awards
- NATIONAL CANCER INSTITUTE [P01CA154303, R01CA154480, K08CA138918, R01CA130988, T32CA009621] Funding Source: NIH RePORTER
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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 I kappa B 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 a lone does not. CYT387 treatment inhibited activation of both NF-kappa B 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.
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