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Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?

Lookup NU author(s): Alice Bradbury, Sally Hall, Professor Nicola Curtin, Dr Yvette Drew

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Abstract

© 2019. The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely to enter S phase with increased RS. These cancer cells become more reliant on their S and G2/M checkpoints, making this an attractive anti-cancer target. Targeting ATR is the focus of many oncology drug pipelines with a number of potent, selective ATR inhibitors developed, four (M6620, M4344, AZD6738 and BAY1895344) are currently in clinical development. Here we summarise the pre-clinical data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and novel targeted agents such as PARP inhibitors. We discuss the current clinical trial data and the challenges of taking ATR inhibitors into the clinic and of identifying biomarkers to aid patient selection.


Publication metadata

Author(s): Bradbury A, Hall S, Curtin N, Drew Y

Publication type: Review

Publication status: Published

Journal: Pharmacology and Therapeutics

Year: 2020

Volume: 207

Print publication date: 01/03/2020

Online publication date: 11/12/2019

Acceptance date: 02/04/2018

ISSN (print): 0163-7258

ISSN (electronic): 1879-016X

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.pharmthera.2019.107450

DOI: 10.1016/j.pharmthera.2019.107450

PubMed id: 31836456


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