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

H Kim, H Xu, E George, D Hallberg, S Kumar… - Nature …, 2020 - nature.com
H Kim, H Xu, E George, D Hallberg, S Kumar, V Jagannathan, S Medvedev, Y Kinose…
Nature communications, 2020nature.com
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 …
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.
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