Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors

Cancer Res. 2019 Feb 1;79(3):452-460. doi: 10.1158/0008-5472.CAN-18-2077. Epub 2018 Dec 10.


The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and PARP inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identify radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquire drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy. SIGNIFICANCE: These findings uncover radiosensitivity as a novel, therapeutically viable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein
  • Cell Cycle Proteins / genetics
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Homologous Recombination / genetics
  • Humans
  • Mad2 Proteins / genetics
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / radiotherapy*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerases / genetics
  • Radiation Tolerance / genetics
  • Telomere-Binding Proteins / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor p53-Binding Protein 1 / genetics*


  • BRCA1 Protein
  • Brca1 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Mad2 Proteins
  • Mad2l2 protein, mouse
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Rif1 protein, mouse
  • SHLD1 protein, human
  • Telomere-Binding Proteins
  • Trp53bp1 protein, mouse
  • Tumor Suppressor Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • Poly(ADP-ribose) Polymerases