Inhibition of the dual function cell cycle and transcription kinase CDK7 is known to affect the viability of cancer cells, but the mechanisms underlying cell line-specific growth control remain poorly understood. Here, we employed a previously developed, highly specific small molecule inhibitor that non-covalently blocks ATP binding to CDK7 (LDC4297) to study the mechanisms underlying cell line-specific growth using a panel of genetically heterogeneous human pancreatic tumor lines as model system. Although LDC4297 diminished both transcription rates and CDK T-loop phosphorylation in a comparable manner, some PDAC lines displayed significantly higher sensitivity than others. We focused our analyses on two well-responsive lines (Mia-Paca2 and Panc89) that, however, showed significant differences in their viability upon extended exposure to limiting LDC4297 concentrations. Biochemical and RNAseq analysis revealed striking differences in gene expression and cell cycle control. Especially the downregulation of a group of cell cycle control genes, among them CDK1/2 and CDC25A/C, correlated well to the observed viability differences in Panc89 versus Mia-Paca2 cells. A parallel downregulation of regulatory pathways supported the hypothesis of a feedforward programmatic effect of CDK7 inhibitors, eventually causing hypersensitivity of PDAC lines.

中文翻译：

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控制关键细胞周期酶的表达驱动 CDK7 在人类 PDAC 细胞中的细胞系特异性功能

已知抑制双重功能细胞周期和转录激酶 CDK7 会影响癌细胞的活力，但细胞系特异性生长控制的潜在机制仍然知之甚少。在这里，我们采用了一种先前开发的、高度特异性的小分子抑制剂，该抑制剂非共价阻断 ATP 与 CDK7 (LDC4297) 的结合，以使用一组遗传异质的人类胰腺肿瘤系作为模型系统来研究细胞系特异性生长的机制。尽管 LDC4297 以类似的方式降低了转录率和 CDK T 环磷酸化，但一些 PDAC 系显示出比其他系显着更高的灵敏度。我们将分析集中在两条反应良好的线（Mia-Paca2 和 Panc89）上，然而，在延长暴露于限制性 LDC4297 浓度时，它们的生存能力显示出显着差异。生化和 RNAseq 分析揭示了基因表达和细胞周期控制的显着差异。特别是一组细胞周期控制基因的下调，其中包括 CDK1/2 和 CDC25A/C，与观察到的 Panc89 与 Mia-Paca2 细胞的活力差异密切相关。调节通路的平行下调支持 CDK7 抑制剂前馈程序效应的假设，最终导致 PDAC 系的超敏反应。与观察到的 Panc89 与 Mia-Paca2 细胞的活力差异很好地相关。调节通路的平行下调支持 CDK7 抑制剂前馈程序效应的假设，最终导致 PDAC 系的超敏反应。与观察到的 Panc89 与 Mia-Paca2 细胞的活力差异很好地相关。调节通路的平行下调支持 CDK7 抑制剂前馈程序效应的假设，最终导致 PDAC 系的超敏反应。