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Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor

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  • Camilla L Christensen
  • Nicholas Kwiatkowski
  • Brian J Abraham
  • Julian Carretero
  • Fatima Al-Shahrour
  • Tinghu Zhang
  • Edmond Chipumuro
  • Grit S Herter-Sprie
  • Esra A Akbay
  • Abigail Altabef
  • Jianming Zhang
  • Takeshi Shimamura
  • Marzia Capelletti
  • Jakob B Reibel
  • Jillian D Cavanaugh
  • Peng Gao
  • Yan Liu
  • Signe R Michaelsen
  • Hans S Poulsen
  • Amir R Aref
  • David A Barbie
  • James E Bradner
  • Rani E George
  • Nathanael S Gray
  • Richard A Young
  • Kwok-Kin Wong
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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.

Original languageEnglish
JournalCancer Cell
Volume26
Issue number6
Pages (from-to)909-22
Number of pages14
ISSN1535-6108
DOIs
Publication statusPublished - 8 Dec 2014

    Research areas

  • Animals, Antineoplastic Agents, Cell Line, Tumor, Cyclin-Dependent Kinases, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, High-Throughput Screening Assays, Humans, Lung Neoplasms, Mice, Molecular Sequence Data, Neoplasms, Experimental, Sequence Analysis, DNA, Small Cell Lung Carcinoma, Transcription Factors, Transcription, Genetic, Xenograft Model Antitumor Assays

ID: 44975051