Targeting triple-negative breast cancers with the Smac-mimetic birinapant
Targeting triple-negative breast cancers with the Smac-mimetic birinapant
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DOI：
10.1038/s41418-020-0541-0
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发表时间：
2020-04-27
影响因子：
12.4
通讯作者：
Silke, John
中科院分区：
文献类型：
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作者：
Lalaoui, Najoua;Merino, Delphine;Silke, John
Smac模拟物靶向凋亡抑制剂（IAP）蛋白，从而抑制它们促进肿瘤细胞死亡的功能。在这里，我们评估了临床前Smac模拟化合物A和临床先导birinapant对乳腺癌细胞的功效。两者在三阴性乳腺癌（TNBC）细胞中表现出有效的体外活性，包括来自患者来源的异种移植物（PDX）模型的那些。使用TNBC和雌激素受体阳性（ER+）乳腺癌的体内PDX模型进一步研究Birinapant。Birinapant在所有TNBC PDX模型中均表现出单药活性，并增强了对多西他赛的反应，后者通过诱导TNF。TCGA数据集的转录组学分析显示，与ER+乳腺癌相比，编码Smac模拟物诱导的细胞死亡的介导物的基因在TNBC中以更高的水平表达，导致与对Smac模拟物的响应性相关的分子特征。此外，响应于Smac模拟物，细胞死亡复合物优先在TNBC中相对于ER+细胞形成。综上所述，我们的研究结果为前瞻性选择乳腺肿瘤中含有有效死亡受体信号通路的患者提供了理论依据，以便在临床上进一步评估birinapant。
Smac mimetics target inhibitor of apoptosis (IAP) proteins, thereby suppressing their function to facilitate tumor cell death. Here we have evaluated the efficacy of the preclinical Smac-mimetic compound A and the clinical lead birinapant on breast cancer cells. Both exhibited potent in vitro activity in triple-negative breast cancer (TNBC) cells, including those from patient-derived xenograft (PDX) models. Birinapant was further studied using in vivo PDX models of TNBC and estrogen receptor-positive (ER+) breast cancer. Birinapant exhibited single agent activity in all TNBC PDX models and augmented response to docetaxel, the latter through induction of TNF. Transcriptomic analysis of TCGA datasets revealed that genes encoding mediators of Smac-mimetic-induced cell death were expressed at higher levels in TNBC compared with ER+ breast cancer, resulting in a molecular signature associated with responsiveness to Smac mimetics. In addition, the cell death complex was preferentially formed in TNBCs versus ER+ cells in response to Smac mimetics. Taken together, our findings provide a rationale for prospectively selecting patients whose breast tumors contain a competent death receptor signaling pathway for the further evaluation of birinapant in the clinic.