Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth
Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth
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DOI：
10.1172/jci75661
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发表时间：
2014-12-01
影响因子：
15.9
通讯作者：
Gillanders, William E.
中科院分区：
文献类型：
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作者：
Barbie, Thanh U.;Alexe, Gabriela;Gillanders, William E.
三阴性乳腺癌（TNBC）是一组异质性癌症，其定义为缺乏激素受体表达和HER 2扩增。在此，我们发现诱导型I κ B激酶相关（IKK相关）激酶IKBKE表达和JAK/STAT通路激活在TNBC的免疫激活亚群中构成细胞因子信号传导网络。我们发现，用CYT 387（TBK 1/IKBKE和JAK信号传导的有效抑制剂）处理培养的IKBKE驱动的乳腺癌细胞会损害增殖，而单独抑制JAK则不会。CYT 387处理抑制NF-κ B和STAT的活化，并破坏这些IKBKE驱动的乳腺癌细胞中促肿瘤细胞因子CCL 5和IL-6的表达。此外，在3D培养模型中，向培养基中添加CCL 5和IL-6不仅促进肿瘤球体分散，而且刺激内皮细胞的增殖和迁移。CYT 387在体内中断细胞因子信号传导损害了IKBKE驱动的TNBC细胞系和患者来源的异种移植物（PDX）的生长。CYT 387疗法与MEK抑制剂的组合特别有效，在TNBC的侵袭性PDX模型中消除肿瘤生长和血管生成。总之，这些发现揭示了IKBKE相关的细胞因子信号传导促进免疫驱动的TNBC的致瘤性，并确定了使用临床可用化合物的潜在治疗策略。
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.