Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.
Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers.
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DOI：
10.1101/gad.262642.115
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发表时间：
2015-08-01
影响因子：
10.5
通讯作者：
Silva JM
中科院分区：
文献类型：
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作者：
Rodriguez-Barrueco R;Yu J;Saucedo-Cuevas LP;Olivan M;Llobet-Navas D;Putcha P;Castro V;Murga-Penas EM;Collazo-Lorduy A;Castillo-Martin M;Alvarez M;Cordon-Cardo C;Kalinsky K;Maurer M;Califano A;Silva JM
罗德里格斯·巴鲁科等人。研究发现，HR−/HER2+ 细胞分泌高水平的 IL-6，诱导 STAT3 的激活，进而促进第二次自分泌刺激，增加 S100A8/9 复合物（钙卫蛋白）的产生和分泌。使用 FDA 批准的药物单独或与 HER2 抑制剂联合抑制 IL-6-JAK2-STAT3-钙卫蛋白轴，可降低 HR-/HER2+ 乳腺癌的致瘤性。 HER2 阳性 (HER2+) 乳腺癌是一个异质性群体，其中激素受体 (HR) 状态影响治疗决策和患者预后。通过将全基因组 RNAi 筛选与调控网络分析相结合，我们确定 STAT3 是 HR−/HER2+ 肿瘤的关键激活的主调节因子，引发这些细胞中的肿瘤依赖性。从机制上讲，HR−/HER2+ 细胞分泌高水平的白介素 6 (IL-6) 细胞因子，诱导 STAT3 激活，进而促进第二次自分泌刺激，增加 S100A8/9 复合物（钙卫蛋白）的产生和分泌。钙卫蛋白水平升高会激活参与增殖和抵抗的信号通路。重要的是，我们证明，使用 FDA 批准的药物单独或与 HER2 抑制剂联合使用，抑制 IL-6–Janus 激酶 2 (JAK2)–STAT3–钙卫蛋白轴，可降低 HR−/HER2+ 乳腺癌的致瘤性，从而开辟新的靶向治疗机会。
Rodriguez-Barrueco et al. found that HR−/HER2+ cells secrete high levels of IL-6, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Inhibition of the IL-6–JAK2–STAT3–calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR−/HER2+ breast cancers. HER2-positive (HER2+) breast adenocarcinomas are a heterogeneous group in which hormone receptor (HR) status influences therapeutic decisions and patient outcome. By combining genome-wide RNAi screens with regulatory network analysis, we identified STAT3 as a critically activated master regulator of HR−/HER2+ tumors, eliciting tumor dependency in these cells. Mechanistically, HR−/HER2+ cells secrete high levels of the interleukin-6 (IL-6) cytokine, inducing the activation of STAT3, which in turn promotes a second autocrine stimulus to increase S100A8/9 complex (calprotectin) production and secretion. Increased calprotectin levels activate signaling pathways involved in proliferation and resistance. Importantly, we demonstrated that inhibition of the IL-6–Janus kinase 2 (JAK2)–STAT3–calprotectin axis with FDA-approved drugs, alone and in combination with HER2 inhibitors, reduced the tumorigenicity of HR−/HER2+ breast cancers, opening novel targeted therapeutic opportunities.