Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Collaborative Center for Translational Mass Spectrometry, The Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
Neuro Oncol. 2022 Nov 2;24(11):1857-1868. doi: 10.1093/neuonc/noac067.
Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer. We report vulnerability to MLN4924 or pevonedistat (a neddylation inhibitor) in a subset of glioblastoma (GBM) preclinical models and identify biomarkers, mechanisms, and signatures of differential response.
GBM sequencing data were queried for genes associated with MLN4924 response status; candidates were validated by molecular techniques. Time-course transcriptomics and proteomics revealed processes implicated in MLN4924 response.
Vulnerability to MLN4924 is associated with elevated S-phase populations, re-replication, and DNA damage. Transcriptomics and shotgun proteomics depict PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between sensitive and resistant models. Loss of PTEN and its nuclear functions is associated with resistance to MLN4924. Time-course proteomics identified elevated TOP2A in resistant models through treatment. TOP2A inhibitors combined with MLN4924 prove synergistic.
We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.
影响蛋白质翻译后功能和周转率的泛素化抑制是癌症治疗的一种很有前途的方法。我们报告了在一小部分脑胶质瘤（GBM）临床前模型中对 MLN4924 或 pevonedistat（一种泛素化抑制剂）的敏感性，并确定了差异反应的生物标志物、机制和特征。
对 GBM 测序数据进行了查询，以寻找与 MLN4924 反应状态相关的基因；通过分子技术对候选基因进行了验证。时间过程转录组学和蛋白质组学揭示了与 MLN4924 反应相关的过程。
对 MLN4924 的敏感性与 S 期细胞群体增加、再复制和 DNA 损伤有关。转录组学和鸟枪法蛋白质组学表明，PTEN 信号、DNA 复制和染色质不稳定途径是敏感和耐药模型之间的重要区别。PTEN 的缺失及其核功能与 MLN4924 的耐药性有关。时间过程蛋白质组学通过治疗发现耐药模型中 TOP2A 的表达升高。TOP2A 抑制剂与 MLN4924 联合使用具有协同作用。
我们表明，PTEN 状态既是 GBM 中 MLN4924 反应的新型生物标志物，也是 TOP2A 抑制剂与 MLN4924 联合使用的脆弱性的标志物。
