Molecular Pathology, Institute of Pathology, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany; Department of Translational Genomics, Medical Faculty, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
Department I of Internal Medicine and Center for Integrated Oncology, University Hospital of Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
Cell Rep. 2017 Sep 19;20(12):2833-2845. doi: 10.1016/j.celrep.2017.08.082.
Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT-rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT-specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients.
激酶抑制剂是靶向癌症治疗的主要手段，但只有少数致癌驱动因素可直接作为药物靶点。通过检测 1505 种激酶抑制剂的活性，我们发现 BRD4-NUT 重排的中线癌（NMC）细胞对 CDK9 抑制剂（CDK9i）具有特异性杀伤作用，并且依赖于 CDK9 和 Cyclin-T1 的表达。我们表明 CDK9i 可在 NMC 细胞中强烈诱导细胞凋亡和 DNA 损伤反应标志物的产生。虽然 CDK9i 和溴结构域抑制都会随着时间的推移导致 Myc 蛋白表达减少，但只有溴结构域抑制会诱导这些细胞分化和 p21 诱导的细胞周期停滞。最后，RNA-seq 和基于 ChIP 的分析揭示了 BRD4-NUT 特异性 CDK9i 诱导的转录延伸扰动。因此，我们的数据为 NMC 细胞对 CDK9i 的基因型依赖性易感性提供了机制基础，这可能与开发针对 NMC 患者的靶向治疗方法相关。
