Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 24, 2020
- Source ID
- 10.1038/s41467-020-17127-2
Entities
People
- Aaron George
- Dorothy Hallberg
- Eric J. Brown
- Fiona Simpkins
- Gordon B. Mills
- Haineng Xu
- Hyoung Kim
- Kevin Ly
- Kyle Devins
- Lauren Schwartz
- Neil F. Johnson
- Priyanka Verma
- Robert B. Scharpf
- Roger A. Greenberg
- Rugang Zhang
- Sergey Medvedev
- Sushil Kumar
- Veena Jagannathan
- Victor Velculescu
- Yasuto Kinose
- Yifan Wang
Organizations
- Adelson Foundation
- National Cancer Institute
- Ovarian Cancer Research Alliance
- Rivkin Center for Ovarian Cancer
- United States Department of Defense
- United States Department of Health and Human Services