A Tale of Two Checkpoints: ATR Inhibition and PD-(L)1 Blockade
- 27 January 2022
- journal article
- review article
- Published by Annual Reviews in Annual Review of Medicine
- Vol. 73 (1), 231-250
- https://doi.org/10.1146/annurev-med-042320-025136
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. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.Keywords
This publication has 85 references indexed in Scilit:
- Combining ATR Suppression with Oncogenic Ras Synergistically Increases Genomic Instability, Causing Synthetic Lethality or Tumorigenesis in a Dosage-Dependent MannerCancer Research, 2010
- Maintaining genome stability at the replication forkNature Reviews Molecular Cell Biology, 2010
- The DNA-damage response in human biology and diseaseNature, 2009
- ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA DamageScience, 2007
- The DNA damage pathway regulates innate immune system ligands of the NKG2D receptorNature, 2005
- Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpointGenes & Development, 2005
- Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategyNature, 2005
- Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymeraseNature, 2005
- Sensing DNA Damage Through ATRIP Recognition of RPA-ssDNA ComplexesScience, 2003
- Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytesInternational Immunology, 1996