title: 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.forename: Thanh U
authors.initials: TU
authors.lastname: Barbie
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.forename: Amir R
authors.initials: AR
authors.lastname: Aref
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Li
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhu
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Imamura
authors.forename: Tran C
authors.initials: TC
authors.lastname: Thai
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Michaela
authors.initials: M
authors.lastname: Bowden
authors.forename: John
authors.initials: J
authors.lastname: Herndon
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Cohoon
authors.forename: Timothy
authors.initials: T
authors.lastname: Fleming
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.forename: William E
authors.initials: WE
authors.lastname: Gillanders
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; C483024:CCL5 protein, human; D018946:Chemokine CCL5; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011743:Pyrimidines; C546012:N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide; D053612:Janus Kinases; D051550:I-kappa B Kinase; C496565:IKBKE protein, human