Abstract 6210: Combination of M1774 and niraparib can overcome ATR and PARP inhibitor resistance in BRCA1 mutated ovarian cancer models
Authors: Hao Jie , Bose Arindam , Sadatrezaei Golbahar , Martignetti David B. , Jiao Yuqing , da Costa Alexandre André B. , Lazaro Jean-Bernard , Kochupurakkal Bose , Nguyen Huy , Parmar Kalindi , D’Andrea Alan D. , Shapiro Geoffrey I. 
Published: April 2023

Abstract
PARP inhibitors are being used in maintenance treatment of BRCA-mutated high-grade serous ovarian cancer (HGSOC). However, de novo and acquired resistance to PARP inhibitors, resulting from restoration of homologous recombination repair or stabilization of replication forks, is a pressing clinical problem. ATR inhibitors are known to reverse both of these mechanisms of PARP inhibitor resistance and are currently in clinical development. In this study, we assessed the activity of a novel ATR inhibitor, M1774, as a monotherapy and in combination with PARP inhibition in HGSOC preclinical models. M1774 exhibited single-agent activity across a panel of ovarian cancer cell lines with induction of DNA damage. We used a panel of BRCA1-mutated patient-derived xenograft (PDX) models of HGSOC with acquired PARP inhibitor resistance and identified two M1774-sensitive models and one M1774-resistant model. M1774 monotherapy demonstrated anti-tumor activity in mice bearing sensitive PDX models of HGSOC with PARP inhibitor resistance. In the M1774-sensitive models, the combination of M1774 and niraparib augmented the degree and durability of response compared with M1774 monotherapy. The combination of M1774 and niraparib also demonstrated synergistic anti-tumor activity in the M1774-resistant model, indicating that the combination could overcome monotherapy resistant to either agent. We also generated organoid cultures from these PDX models. Treatment of the organoid models with M1774, niraparib or the combination faithfully recapitulated the anti-tumor activities seen in vivo. Mechanistically, M1774-resistant organoid cultures demonstrated stable replication forks and an absence of replication stress. The combination of M1774 with niraparib resulted in destabilization of the replication forks. In contrast, M1774-sensitive organoids exhibited unstable replication forks, which were further destabilized by the niraparib combination. In addition, the sensitive models demonstrated higher basal levels of replication stress, as detected by increased levels of phospho-RPA. Collectively, these results indicate that the combination of M1774 and niraparib can overcome PARP inhibitor resistance and ATR inhibitor resistance in BRCA1-mutant ovarian cancer PDX models and demonstrate the utility of organoid cultures for discerning mechanisms of resistance and strategies to restore drug sensitivity. Combined M1774-mediated ATR inhibition and PARP inhibition may be a promising therapeutic strategy for the treatment of ovarian cancer.
Citation Format: Jie Hao, Arindam Bose, Golbahar Sadatrezaei, David B. Martignetti, Yuqing Jiao, Alexandre André B. da Costa, Jean-Bernard Lazaro, Bose Kochupurakkal, Huy Nguyen, Kalindi Parmar, Alan D. D’Andrea, Geoffrey I. Shapiro. Combination of M1774 and niraparib can overcome ATR and PARP inhibitor resistance in BRCA1 mutated ovarian cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6210.