Targeting Transcriptional Addictions in Small Cell Lung Cancer with a Covalent CDK7 Inhibitor (Affymetrix)

Small cell lung cancer (SCLC) is an aggressive disease with high mortality. The identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library we observe that SCLC is sensitive to transcription-targeting drugs, and in particular to THZ1, a newly identified covalent inhibitor of cyclin-dependent kinase 7 (CDK7). We find that expression of super-enhancer associated transcription factor genes including MYC family proto-oncogenes and neuroendocrine lineage-specific factors are highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a novel treatment paradigm for targeted SCLC therapy. Microarray expression in small cell lung cancer lines treated with DMSO or THZ1

小细胞肺癌（Small cell lung cancer, SCLC）是一种侵袭性强、死亡率极高的恶性疾病。靶向SCLC生物学特性的有效药理策略的开发已是迫切需求。本研究通过针对多样化化学文库的高通量细胞筛选，发现SCLC对靶向转录的药物具有敏感性，尤其对新型共价细胞周期蛋白依赖性激酶7（CDK7）抑制剂THZ1敏感。我们发现，包括MYC家族原癌基因与神经内分泌谱系特异性因子在内的超级增强子（Super-enhancer）相关转录因子基因的表达，对THZ1治疗具有高度易感性。我们提出，上述转录因子的下调可部分促成SCLC对转录抑制剂的敏感性，且THZ1为靶向SCLC治疗提供了一种全新的治疗范式。经二甲基亚砜（Dimethyl sulfoxide, DMSO）或THZ1处理的小细胞肺癌细胞系的微阵列表达数据