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

Pharmacol Ther

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; Northern Centre for Cancer Care, Newcastle upon Tyne NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK. Electronic address:

Published: March 2020

AI Article Synopsis

  • The DNA damage response (DDR) detects and repairs DNA damage, with ATR protein playing a crucial role in managing replication stress and signaling for cell cycle checkpoints.* * Cancer cells often lose G1 checkpoint control and rely heavily on S and G2/M checkpoints due to increased replication stress, making ATR an important target for cancer therapy.* * Several ATR inhibitors are in clinical development, with research focusing on their effectiveness as standalone treatments and in combination with other therapies, while also addressing challenges in clinical application and patient selection.*

Article Abstract

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.

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Source
http://dx.doi.org/10.1016/j.pharmthera.2019.107450DOI Listing

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