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

Hyoung Kim,Eric J Brown,Neil Johnson,Rugang Zhang,Sergey Medvedev,Priyanka Verma,Lauren Schwartz ,Erin George,Sushil Kumar,Yasuto Kinose,Haineng Xu,Gordon B Mills,Victor E Velculescu,Kyle M Devins ,Kévin Ly ,Dorothy Hallberg,Robert B Scharpf,Yifan Wang,Veena Jagannathan,Roger A Greenberg,Fiona Simpkins

doi:10.1038/s41467-020-17127-2

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.

Highlights

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi)
PARPi and platinum-resistant models were developed from BRCA1MUT and BRCA2MUT parental cell lines to emulate treatment paradigms used in the clinic, and identify vulnerabilities for therapeutic targets in the context of acquired drug resistance
BRCA1MUT (JHOS4-PR, PR1, PR2) and BRCA2MUT (PEO1-PR, PR1, PR2) cell lines were developed after long-term continuous treatment (~1.5 years) in olaparib, an FDA approved PARPi

Summary

Introduction

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). 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. Despite advances in understanding the genetics of highgrade serous ovarian cancer (HGSOC)[1], standard frontline care remains surgical debulking and platinum-based chemotherapy With this approach, more than 80% of women with HGSOC recur[2,3] and over 14,000 die yearly in the United States[4].

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Conclusion