EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

Cancer Cell. 2018 Feb 12;33(2):202-216.e6. doi: 10.1016/j.ccell.2017.12.009. Epub 2018 Jan 18.


Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

Keywords: CDK12; DNA damage repair; EWS/FLI; Ewing sarcoma; PARP inhibitors; THZ1; THZ531; synthetic lethal.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin-Dependent Kinases / drug effects*
  • Cyclin-Dependent Kinases / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Oncogene Proteins, Fusion / drug effects
  • Oncogene Proteins, Fusion / genetics
  • Phenylenediamines / pharmacology*
  • Proto-Oncogene Protein c-fli-1 / drug effects
  • Proto-Oncogene Protein c-fli-1 / genetics*
  • Pyrimidines / pharmacology*
  • RNA-Binding Protein EWS / drug effects
  • RNA-Binding Protein EWS / genetics*
  • Sarcoma, Ewing / genetics*
  • Synthetic Lethal Mutations / drug effects
  • Synthetic Lethal Mutations / genetics


  • Oncogene Proteins, Fusion
  • Phenylenediamines
  • Proto-Oncogene Protein c-fli-1
  • Pyrimidines
  • RNA-Binding Protein EWS
  • THZ1 compound
  • CDK12 protein, human
  • Cyclin-Dependent Kinases