Poly (ADP-Ribose) Polymerase Inhibitor Olaparib-Resistant BRCA1-Mutant Ovarian Cancer Cells Demonstrate Differential Sensitivity to PARP Inhibitor Rechallenge

Cells. 2024 Nov 7;13(22):1847. doi: 10.3390/cells13221847.

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) show cytotoxicity in homologous recombination deficiency (HRD) seen in BRCA-mutant ovarian cancer (OvCa). Despite initial responses, resistance often develops. The reintroduction of different PARPis, such as niraparib or rucaparib, has shown some clinical activity in BRCA mutation-associated OvCa patients with prior olaparib treatment, yet the underlying mechanisms remain unclear. To investigate the differential sensitivity to different PARPis, we established an olaparib-resistant BRCA1-mutant OvCa cell line (UWB-OlaJR) by exposing UWB1.289 cells to gradually increasing concentrations of olaparib. UWB-OlaJR exhibited restored HR capability without BRCA1 reversion mutation or increased drug efflux. We examined cell viability, DNA damage, and DNA replication fork dynamics in UWB-OlaJR treated with various PARPis. UWB-OlaJR exhibits varying sensitivity to PARPis, showing cross-resistance to veliparib and talazoparib, and sensitivity with increased cytotoxicity to niraparib and rucaparib. Indeed, DNA fiber assay reveals that niraparib and rucaparib cause higher replication stress than the others. Moreover, S1 nuclease fiber assay shows that niraparib and rucaparib induce greater DNA single-strand gaps than other PARPis, leading to increased DNA damage and cell death. Our study provides novel insights into differential PARPi sensitivity in olaparib-resistant BRCA-mutant OvCa, which requires further investigation of inter-agent differences in large prospective studies.

Keywords: BRCA-mutation; ovarian cancer; poly (ADP-ribose) polymerase inhibitor resistance; replication fork; single-strand breaks.

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • DNA Replication / drug effects
  • Drug Resistance, Neoplasm* / drug effects
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Humans
  • Mutation* / genetics
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology
  • Phthalazines* / pharmacology
  • Piperazines* / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology

Substances

  • Poly(ADP-ribose) Polymerase Inhibitors
  • olaparib
  • Phthalazines
  • Piperazines
  • BRCA1 Protein
  • BRCA1 protein, human