Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models

Nat Commun. 2020 Jul 24;11(1):3726. doi: 10.1038/s41467-020-17127-2.


Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • BRCA2 Protein / metabolism
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cyclins / metabolism
  • Drug Combinations
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Knockout Techniques
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics
  • Platinum / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Rad51 Recombinase / metabolism
  • Stem Cells
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • CCNE2 protein, human
  • Cyclins
  • Drug Combinations
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Protein Kinase Inhibitors
  • Platinum
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • RAD51 protein, human
  • Rad51 Recombinase