Targeting Transcriptional Addictions in Small Cell Lung Cancer With a Covalent CDK7 Inhibitor

Cancer Cell. 2014 Dec 8;26(6):909-922. doi: 10.1016/j.ccell.2014.10.019.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • High-Throughput Screening Assays
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Mice
  • Molecular Sequence Data
  • Neoplasms, Experimental
  • Sequence Analysis, DNA
  • Small Cell Lung Carcinoma
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Transcription Factors
  • Cyclin-Dependent Kinases

Associated data

  • GEO/GSE62614