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

• Published in: Annual review of medicine Vol. 73; no. 1; pp. 231 - 250
• Main Authors: Ngoi, Natalie Y.L, Peng, Guang, Yap, Timothy A
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 27.01.2022; Annual Reviews, Inc
• Subjects: Ataxia telangiectasia; ATR inhibitors; cancer therapy; Cell activation; Cell cycle; CHK1 protein; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA repair; drug development; immune checkpoint blockade; immune modulation; Immune response; Immunomodulation; Innate immunity; Tumor microenvironment; Tumors; drug development; cancer therapy; immune modulation; ATR inhibitors; immune checkpoint blockade
• ISSN: 0066-4219; 1545-326X
• DOI: 10.1146/annurev-med-042320-025136

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.