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Single-Molecule Imaging of EWS-FLI1 Condensates Assembling on DNA
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EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma

Amanda Balboni Iniguez1, Björn Stolte2, Emily Jue Wang1

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Cancer Cell
|January 24, 2018
PubMed

Insights

Ewing sarcoma shows sensitivity to CDK inhibitors THZ1 and THZ531, which target oncogenic transcription factors. Combining these with PARP inhibitors demonstrates significant synergy in preclinical models, offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Many cancers are driven by transcription factors that are challenging to target with drugs.
  • Transcriptional inhibitors represent a promising therapeutic strategy for these cancers.

Purpose of the Study:

  • To identify novel therapeutic vulnerabilities in Ewing sarcoma.
  • To investigate the efficacy of CDK7/12/13 and CDK12/13 inhibitors in Ewing sarcoma models.

Main Methods:

  • Chemical genomics screening to identify drug sensitivities.
  • In vitro and in vivo studies using Ewing sarcoma cell lines and patient-derived xenografts (PDX).
  • Assays for cell viability, DNA damage, and hematopoietic toxicity.

Main Results:

  • Ewing sarcoma exhibits preferential sensitivity to THZ1, a CDK7/12/13 inhibitor.
  • THZ531, a selective CDK12/13 inhibitor, impairs DNA damage repair in an EWS/FLI-dependent manner.
  • Combination therapy with THZ1/THZ531 and PARP inhibitors showed significant synergy in preclinical models, including PDX models, without hematopoietic toxicity.

Conclusions:

  • A synthetic lethal relationship exists between EWS/FLI expression and response to THZ1/THZ531.
  • The combination of CDK inhibitors and PARP inhibitors is a promising therapeutic strategy for Ewing sarcoma.
  • This combination demonstrates efficacy in vivo without significant side effects.
Keywords:
CDK12DNA damage repairEWS/FLIEwing sarcomaPARP inhibitorsTHZ1THZ531synthetic lethal

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