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

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). This study demonstrates that acquired PARPi resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). PARPi-resistant cells show significantly increased sensitivity to ATRi when combined with PARPi (PARPi-ATRi). This sensitivity correlates with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis across various resistant models. Surprisingly, BRCA reversion mutations and RAD51 foci formation are not always observed in acquired PARPi resistance models, suggesting alternative resistance mechanisms. However, regardless of the resistance mechanism, complete and durable therapeutic responses to PARPi-ATRi significantly increasing survival are observed in patient-derived xenografts (PDXs). These findings suggest PARPi-ATRi is a highly promising strategy for overcoming PARPi and platinum resistance in OVCA.

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, Fiona Simpkins