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

Hyoung Kim, Haineng Xu, Erin George, Dorothy Hallberg, Sushil Kumar, Veena Jagannathan, Sergey Medvedev, Yasuto Kinose, Kyle Devins, Priyanka Verma, Kevin Ly, Yifan Wang, Roger A. Greenberg, Lauren Schwartz, Neil Johnson, Robert B. Scharpf, Gordon B. Mills, Rugang Zhang, Victor E. Velculescu, Eric J. Brown and Fiona Simpkins ()
Additional contact information
Hyoung Kim: University of Pennsylvania
Haineng Xu: University of Pennsylvania
Erin George: University of Pennsylvania
Dorothy Hallberg: Johns Hopkins University School of Medicine
Sushil Kumar: University of Pennsylvania
Veena Jagannathan: University of Pennsylvania
Sergey Medvedev: University of Pennsylvania
Yasuto Kinose: University of Pennsylvania
Kyle Devins: University of Pennsylvania
Priyanka Verma: University of Pennsylvania
Kevin Ly: University of Pennsylvania
Yifan Wang: Fox Chase Cancer Center
Roger A. Greenberg: University of Pennsylvania
Lauren Schwartz: University of Pennsylvania
Neil Johnson: Fox Chase Cancer Center
Robert B. Scharpf: Johns Hopkins University School of Medicine
Gordon B. Mills: Oregon Health & Science University School of Medicine
Rugang Zhang: The Wistar Institute
Victor E. Velculescu: Johns Hopkins University School of Medicine
Eric J. Brown: University of Pennsylvania
Fiona Simpkins: University of Pennsylvania

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17127-2

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DOI: 10.1038/s41467-020-17127-2

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