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Efficacy of ATR inhibitors as single agents in Ewing sarcoma

Maria Nieto-Soler1, Isabel Morgado-Palacin1, Vanesa Lafarga1

  • 1Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Oncotarget
|September 1, 2016
PubMed

Insights

Ewing sarcomas (ES) exhibit high replication stress, making them dependent on the ATR pathway. ATR inhibitors show promise as a novel therapeutic strategy for this pediatric bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Ewing sarcomas (ES) are aggressive pediatric bone tumors driven by specific genetic translocations, commonly EWS/FLI1.
  • Current treatments for ES rely on DNA-damaging agents, but the underlying mechanisms of sensitivity are not fully understood.
  • Replication stress (RS), a source of DNA damage in cancer, is regulated by ATR and CHK1 kinases.

Purpose of the Study:

  • To investigate the role of endogenous replication stress in Ewing sarcomas.
  • To determine the dependency of ES cells on the ATR pathway.
  • To evaluate the therapeutic potential of ATR inhibitors in Ewing sarcomas.

Main Methods:

  • Assessed endogenous replication stress levels in ES cell lines.
  • Utilized ATR inhibitors in in vitro and in vivo models of ES.
  • Examined the effect of oncogenic translocations (EWS/FLI1, EWS/ERG) on ATR inhibitor sensitivity.

Main Results:

  • Ewing sarcomas exhibit significant endogenous replication stress.
  • ES cells demonstrate a strong dependence on the ATR pathway for survival.
  • ATR inhibitors displayed in vitro toxicity against ES cell lines and in vivo efficacy in xenograft models.
  • Expression of EWS/FLI1 or EWS/ERG sensitized non-ES cells to ATR inhibitors.

Conclusions:

  • Ewing sarcomas are highly sensitive to replication stress due to high endogenous levels.
  • The ATR pathway is a critical dependency in Ewing sarcomas.
  • ATR inhibitors represent a promising targeted therapy for Ewing sarcomas, warranting further clinical investigation.
Keywords:
ATRDNA repairEwing sarcomacancerreplication stress

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