ATR Inhibition Preferentially Targets Homologous Recombination-Deficient Tumor Cells

Oncogene. 2015 Jun;34(26):3474-81. doi: 10.1038/onc.2014.276. Epub 2014 Sep 1.

Abstract

Homologous recombination (HR) is required for faithful repair of double-strand DNA breaks. Defects in HR repair cause severe genomic instability and challenge cellular viability. Paradoxically, various cancers are HR defective and have apparently acquired characteristics to survive genomic instability. We aimed to identify these characteristics to uncover therapeutic targets for HR-deficient cancers. Cytogenetic analysis of 1143 ovarian cancers showed that the degree of genomic instability was correlated to amplification of replication checkpoint genes ataxia telangiectasia and Rad3-related kinase (ATR) and CHEK1. To test whether genomic instability leads to increased reliance on replication checkpoint signaling, we inactivated Rad51 to model HR-related genomic instability. Rad51 inactivation caused defective HR repair and induced aberrant replication dynamics. Notably, inhibition of Rad51 led to increased ATR/checkpoint kinase-1 (Chk1)-mediated replication stress signaling. Importantly, inhibition of ATR or Chk1 preferentially killed HR-deficient cancer cells. Combined, our data show that defective HR caused by Rad51 inhibition results in differential sensitivity for ATR and Chk1 inhibitors, implicating replication checkpoint kinases as potential drug targets for HR-defective cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Checkpoint Kinase 1
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • HeLa Cells
  • Homologous Recombination / genetics*
  • Humans
  • MCF-7 Cells
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Protein Kinases / genetics
  • Pyrazines / therapeutic use*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sulfones / therapeutic use*
  • Thiophenes / therapeutic use
  • Urea / analogs & derivatives
  • Urea / therapeutic use

Substances

  • 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
  • 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide
  • Antineoplastic Agents
  • Pyrazines
  • Sulfones
  • Thiophenes
  • Urea
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1