Abstract 1055: Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress and enhances the chemotherapeutic activity of widely used DNA damaging agents

Abstract

Abstract Purpose: Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of cancer patients for predicting activity and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. Experimental design: The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. Results: M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Conclusions: M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344. Citation Format: Ukhyun Jo, Ilya Senatorov, Astrid Zimmermann, Liton Kumar Saha, Yasuhisa Murai, Se Hyun Kim, Vinodh N Rajapakse, Fathi Elloumi, Nobuyuki Takahashi, Christopher Schultz, Anish Thomas, Frank Zenke, Yves Pommier. Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress and enhances the chemotherapeutic activity of widely used DNA damaging agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1055.