Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cancer Cell. 2014 Dec 8;26(6):909-922. doi: 10.1016/j.ccell.2014.10.019.
Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and 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, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is 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 prototype drug for tailored SCLC therapy.
小细胞肺癌（SCLC）是一种具有高死亡率的侵袭性疾病，因此需要寻找有效的药物来靶向 SCLC 生物学特性。我们利用多样化化学文库的高通量细胞筛选发现，SCLC 对转录靶向药物敏感，特别是一种新发现的周期蛋白依赖性激酶 7 的共价抑制剂 THZ1。我们发现，超级增强子相关转录因子基因的表达，包括 MYC 家族原癌基因和神经内分泌谱系特异性因子，对 THZ1 治疗非常敏感。我们提出，这些转录因子的下调部分导致 SCLC 对转录抑制剂的敏感性，THZ1 是针对 SCLC 治疗的原型药物。
