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. BrownFiona Simpkins

    Research output: Contribution to journalArticlepeer-review

    8 Scopus citations

    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.

    Original languageEnglish (US)
    Article number3726
    JournalNature communications
    Volume11
    Issue number1
    DOIs
    StatePublished - Dec 1 2020

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

    Fingerprint Dive into the research topics of 'Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models'. Together they form a unique fingerprint.

    Cite this