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Genome-wide CRISPR screens reveal synthetic lethality of RNASEH2 deficiency and ATR inhibition

Chao Wang1, Gang Wang2, Xu Feng1

  • 1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Oncogene
|December 12, 2018
PubMed

Insights

Identifying genes that increase cancer cell sensitivity to ATR inhibitors is crucial. RNASEH2 deficiency was found to be synthetically lethal with ATR inhibition, suggesting its potential as a therapeutic biomarker.

Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Ataxia telangiectasia mutated and RAD3 related (ATR) protein kinase is vital for DNA replication, repair, and cell cycle control during replication stress.
  • ATR inhibition is a promising cancer therapeutic strategy.
  • Identifying genetic vulnerabilities to ATR inhibition can enhance treatment efficacy.

Purpose of the Study:

  • To identify genes that confer hypersensitivity to ATR inhibition.
  • To investigate the therapeutic potential of targeting RNASEH2 deficiency in conjunction with ATR inhibition.

Main Methods:

  • CRISPR/Cas9-based whole-genome screens were performed in three cell lines treated with the ATR inhibitor AZD6738.
  • In vitro and in vivo studies were conducted to validate findings.
  • RNASEH2B protein levels were assessed in prostate adenocarcinoma patient-derived xenograft (PDX) samples.

Main Results:

  • Genome-wide screens revealed comprehensive ATR inhibitor sensitivity profiles.
  • RNASEH2 deficiency was demonstrated to be synthetically lethal with ATR inhibition.
  • RNASEH2-deficient cells showed increased DNA damage and underwent apoptosis or senescence upon AZD6738 treatment.
  • Decreased RNASEH2B protein levels were observed in prostate adenocarcinoma PDX samples.

Conclusions:

  • RNASEH2 deficiency creates synthetic lethality with ATR inhibition.
  • ATR inhibition may benefit cancer patients with reduced RNASEH2 levels.
  • RNASEH2 warrants further investigation as a predictive biomarker for ATR inhibitor therapy.

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