Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Mol Cancer Ther. 2022 Sep 6;21(9):1430-1438. doi: 10.1158/1535-7163.MCT-21-0891.
Small cell lung cancers (SCLC) are highly aggressive, and currently there are no available targeted therapies. To identify clinically actionable drug combinations, we analyzed our previously reported chemogenomics screens and identified a synergistically cytotoxic combination of the topoisomerase I (TOP1) inhibitor topotecan and cycle-dependent kinase 7 (CDK7) inhibitor THZ1. Topotecan causes cell death by generating TOP1-induced DNA breaks and DNA-protein cross-links (TOP1-DPC) that require proteolysis by the ubiquitin-proteasome pathway for their repair. We find that inhibition of the transcriptional kinase CDK7 by THZ1 induces ubiquitin-mediated proteasomal degradation of RNA polymerase II and prevents the proteasomal degradation of TOP1-DPCs. We provide a mechanistic basis for combinatorial targeting of transcription using selective inhibitors of CDK7 and TOP1 in clinical trials to advance SCLC therapeutics.
小细胞肺癌（SCLC）具有高度侵袭性，目前尚无可用的靶向治疗方法。为了确定具有临床可操作性的药物组合，我们分析了之前报道的化学基因组筛选结果，发现拓扑异构酶 I（TOP1）抑制剂拓扑替康和周期蛋白依赖性激酶 7（CDK7）抑制剂 THZ1 具有协同细胞毒性。拓扑替康通过产生 TOP1 诱导的 DNA 断裂和 DNA-蛋白质交联（TOP1-DPC）导致细胞死亡，这些断裂和交联需要通过泛素-蛋白酶体途径进行蛋白水解来修复。我们发现，THZ1 抑制转录激酶 CDK7 会诱导 RNA 聚合酶 II 的泛素介导的蛋白酶体降解，并阻止 TOP1-DPC 的蛋白酶体降解。我们为在临床试验中使用 CDK7 和 TOP1 的选择性抑制剂进行转录的联合靶向治疗提供了机制基础，以推进 SCLC 的治疗。
