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Kim H , Xu H , George E , Hallberg D , Kumar S , Jagannathan V , Medvedev S , Kinose Y , Devins K , Verma P , Ly K , Wang Y , Greenberg RA , Schwartz L , Johnson N , Scharpf RB , Mills GB , Zhang R , Velculescu VE , Brown EJ , Simpkins F
Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
Nat Commun. 2020 Jul 24;11(1) :3726
PMID: 32709856   
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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.
Notes
2041-1723 Kim, Hyoung Orcid: 0000-0002-9975-8545 Xu, Haineng Orcid: 0000-0001-7195-4897 George, Erin Hallberg, Dorothy Kumar, Sushil Jagannathan, Veena Medvedev, Sergey Kinose, Yasuto Devins, Kyle Verma, Priyanka Ly, Kevin Wang, Yifan Greenberg, Roger A Schwartz, Lauren Johnson, Neil Scharpf, Robert B Mills, Gordon B Orcid: 0000-0002-0144-9614 Zhang, Rugang Orcid: 0000-0002-7255-2360 Velculescu, Victor E Orcid: 0000-0003-1195-438x Brown, Eric J Simpkins, Fiona Orcid: 0000-0002-0840-2368 5R37CA215436-02/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ 1P50CA228991/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ 5R01CA189743/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA006973/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA121113/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA217685/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ OC150336/U.S. Department of Defense (United States Department of Defense)/ Journal Article Nat Commun. 2020 Jul 24;11(1):3726. doi: 10.1038/s41467-020-17127-2.