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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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
  • Hans S Poulsen
  • Amir R Aref
  • David A Barbie
  • James E Bradner
  • Rani E George
  • Nathanael S Gray
  • Richard A Young
  • Kwok-Kin Wong
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.
TidsskriftCancer Cell
Udgave nummer6
Sider (fra-til)909-922
Antal sider14
StatusUdgivet - dec. 2014

ID: 135224591