Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
Cancer Cell. 2013 Jul 8;24(1):75-89. doi: 10.1016/j.ccr.2013.05.005. Epub 2013 Jun 20.
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
MYCN 扩增是人类神经内分泌肿瘤（包括神经母细胞瘤）亚群的驱动突变。目前尚无针对 MYCN 编码蛋白 N-Myc 的靶向小分子药物。N-Myc 与 Aurora-A 激酶形成复合物，该复合物可保护 N-Myc 免受蛋白酶体降解。尽管 N-Myc 的稳定并不需要 Aurora-A 的催化活性，但我们在这里表明，两种 Aurora-A 抑制剂 MLN8054 和 MLN8237 可破坏 Aurora-A/N-Myc 复合物，并促进 Fbxw7 泛素连接酶介导的 N-Myc 降解。破坏 Aurora-A/N-Myc 复合物可抑制 N-Myc 依赖性转录，与 MYCN 驱动的神经母细胞瘤小鼠模型中的肿瘤消退和延长生存期相关。我们的结论是，Aurora-A 是一个可及的靶点，使 N-Myc 不稳定成为一种可行的治疗策略。
