Novel and Highly Potent ATR Inhibitor M4344 Kills Cancer Cells With Replication Stress, and Enhances the Chemotherapeutic Activity of Widely Used DNA Damaging Agents

Mol Cancer Ther. 2021 Aug;20(8):1431-1441. doi: 10.1158/1535-7163.MCT-20-1026. Epub 2021 May 27.

Abstract

Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of patients with cancer 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. 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. We demonstrate that 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. Taken together, 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.

Trial registration: ClinicalTrials.gov NCT02278250 NCT04149145.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Cell Proliferation
  • DNA Replication*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Irinotecan / administration & dosage
  • Isoxazoles / administration & dosage
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Morpholines / administration & dosage
  • Pyrazines / administration & dosage
  • Pyrazoles / administration & dosage
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / metabolism
  • Small Cell Lung Carcinoma / pathology
  • Topotecan / administration & dosage
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • BAY 1895344
  • Isoxazoles
  • Morpholines
  • Pyrazines
  • Pyrazoles
  • Deoxycytidine
  • Irinotecan
  • Topotecan
  • gemcitabine
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • berzosertib

Associated data

  • ClinicalTrials.gov/NCT02278250
  • ClinicalTrials.gov/NCT04149145