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Annual Review of Medicine

Volume 73, 2022

A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade

Abstract

Innate immunity and the DNA damage response (DDR) pathway are inextricably linked. Within the DDR, ataxia telangiectasia and Rad3-related (ATR) is a key kinase responsible for sensing replication stress and facilitating DNA repair through checkpoint activation, cell cycle arrest, and promotion of fork recovery. Recent studies have shed light on the immunomodulatory role of the ATR-CHK1 pathway in the tumor microenvironment and the specific effects of ATR inhibition in stimulating an innate immune response. With several potent and selective ATR inhibitors in developmental pipelines, the combination of dual ATR and PD-(L)1 blockade has attracted increasing interest in cancer therapy. In this review, we summarize the clinical and preclinical data supporting the combined inhibition of ATR and PD-(L)1, discuss the potential challenges surrounding this approach, and highlight biomarkers relevant for selected patients who are most likely to benefit from the blockade of these two checkpoints.

Keyword(s): ATR inhibitors, cancer therapy, drug development, immune checkpoint blockade, immune modulation
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2022-01-27
2024-05-13
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/content/journals/10.1146/annurev-med-042320-025136
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A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade
Annual Review of Medicine 73, 231 (2022); https://doi.org/10.1146/annurev-med-042320-025136
/content/journals/10.1146/annurev-med-042320-025136
/content/journals/10.1146/annurev-med-042320-025136
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