TY - JOUR
T1 - Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models
AU - Kim, Hyoung
AU - Xu, Haineng
AU - George, Erin
AU - Hallberg, Dorothy
AU - Kumar, Sushil
AU - Jagannathan, Veena
AU - Medvedev, Sergey
AU - Kinose, Yasuto
AU - Devins, Kyle
AU - Verma, Priyanka
AU - Ly, Kevin
AU - Wang, Yifan
AU - Greenberg, Roger A.
AU - Schwartz, Lauren
AU - Johnson, Neil
AU - Scharpf, Robert B.
AU - Mills, Gordon B.
AU - Zhang, Rugang
AU - Velculescu, Victor E.
AU - Brown, Eric J.
AU - Simpkins, Fiona
N1 - Funding Information:
We acknowledge Dr. Wei-Ting Hwang (UPENN Epidemiology and Biostats) for her guidance in statistical analysis, Dr. Taehyoung Kim (UPENN Bioinformatics Core) for assistance with RPPA analysis, Juanita Ezemba and Benjamin Ferman (UPENN OCRC) for their assistance with PDX studies. Funding is from Basser Team Science Grant (Simpkins, Brown, Zhang), NIH 5R37CA215436-02 (Simpkins) and SPORE 1P50CA228991 (Simpkins, Brown, Zhang), Department of Defense OC150336 (Simpkins), Rivkin (Simpkins) and Kaleidoscope of Hope Foundation (Simpkins), 5R01CA189743 (Brown), NIH Grant CA121113 and CA006973 (Velculescu) and CA217685 (Mills), Ovarian Cancer Research Foundation (Mills, Zhang), and Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Mills, Velculescu).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-17127-2
DO - 10.1038/s41467-020-17127-2
M3 - Article
C2 - 32709856
AN - SCOPUS:85088361835
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3726
ER -