Amplification of MYCN is a poor prognostic feature in neuroblastoma (NBL) indicating aggressive disease. We and others have shown BET bromodomain inhibitors (BETi) target MYCN indirectly by downregulating its transcription. Here we sought to identify agents that synergize with BETi and to identify biomarkers of resistance. We previously performed a viability screen of ∼1,900 oncology-focused compounds combined with BET bromodomain inhibitors against MYCN-amplified NBL cell lines. Reanalysis of our screening results prominently identified inhibitors of aurora kinase A (AURKAi) to be highly synergistic with BETi. We confirmed the anti-proliferative effects of several BETi+AURKAi combinations in MYCN-amplified NBL cell lines. Compared to single agents, these combinations cooperated to decrease levels of N-myc. We treated both TP53-wild type and mutant, MYCN-amplified cell lines with the BETi JQ1 and the AURKAi Alisertib. The combination had improved efficacy in the TP53-WT context, notably driving apoptosis in both genetic backgrounds. JQ1+Alisertib combination treatment of a MYCN-amplified, TP53-null or TP53-restored genetically engineered mouse model of NBL prolonged survival better than either single agent. This was most profound with TP53 restored, with marked tumor shrinkage and apoptosis induction in response to combination JQ1+Alisertib. BETi+AURKAi in MYCN-amplified NBL, particularly in the context of functional TP53, provided anti-tumor benefits in preclinical models. This combination should be studied more closely in a pediatric clinical trial.

MYCN 的扩增是神经母细胞瘤 (NBL) 的不良预后特征，表明侵袭性疾病。我们和其他人已经证明 BET 溴结构域抑制剂 (BETi)通过下调其转录来间接靶向MYCN。在这里，我们试图确定与 BETi 协同作用的药物并确定耐药性生物标志物。我们之前对 1,900 种以肿瘤学为重点的化合物与 BET 溴结构域抑制剂联合进行了针对MYCN扩增的 NBL 细胞系的活力筛选。对我们筛选结果的重新分析显着地确定了与 BETi 高度协同的极光激酶 A (AURKAi) 抑制剂。我们证实了几种 BETi+AURKAi 组合在MYCN 中的抗增殖作用- 扩增的 NBL 细胞系。与单一药剂相比，这些组合合作降低了 N-myc 的水平。我们用BETi JQ1 和 AURKAi Alisertib处理了TP53野生型和突变体、MYCN扩增的细胞系。该组合在TP53- WT 环境中具有改善的功效，特别是在两种遗传背景下都可驱动细胞凋亡。一个的JQ1 +阿立塞替组合治疗MYCN -amplified，TP53 -null或TP53 -restored NBL的遗传工程化小鼠模型延长生存比任一单一药剂。这对TP53 来说是最深刻的JQ1+Alisertib 组合后，显着的肿瘤缩小和细胞凋亡诱导恢复。MYCN扩增的 NBL 中的BETi+AURKAi ，特别是在功能性TP53的背景下，在临床前模型中提供了抗肿瘤益处。应在儿科临床试验中更仔细地研究这种组合。