Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers

Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers

Abstract ADAR1 is an RNA editing enzyme which prevents autoimmunity by blocking interferon responses triggered by cytosolic RNA sensors, and is a potential target in immuno-oncology. However, predictive biomarkers for ADAR1 inhibition are lacking. Using multiple in vitro and in vivo systems, we show...

Full description

Saved in:
Bibliographic Details
Main Authors: Roman M. Chabanon, Liudmila Shcherbakova, Magali Lacroix-Triki, Marine Aglave, Jean Zeghondy, Victor Kriaa, Antoine Gougé, Marlène Garrido, Elodie Edmond, Ludovic Bigot, Dragomir B. Krastev, Rachel Brough, Stephen J. Pettitt, Thibault Thomas-Bonafos, Robert Samstein, Christophe Massard, Marc Deloger, Andrew NJ Tutt, Fabrice Barlesi, Yohann Loriot, Suzette Delaloge, Marcel Tawk, Cindy Degerny, Yea-Lih Lin, Barbara Pistilli, Philippe Pasero, Christopher J. Lord, Sophie Postel-Vinay
Format: Article
Language:English
Published: Nature Portfolio 2025-07-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-62309-5
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract ADAR1 is an RNA editing enzyme which prevents autoimmunity by blocking interferon responses triggered by cytosolic RNA sensors, and is a potential target in immuno-oncology. However, predictive biomarkers for ADAR1 inhibition are lacking. Using multiple in vitro and in vivo systems, we show that BRCA1/2 and ADAR1 are synthetically lethal, and that ADAR1 activity is upregulated in BRCA1/2-mutant cancers. ADAR1 depletion in BRCA1-mutant cells causes an increase in R-loops and consequently, an upregulation of cytosolic nucleic acid sensing pattern recognition receptors (PRR), events which are associated with a tumor cell-autonomous type I interferon and integrated stress response. This ultimately causes autocrine interferon poisoning. Consistent with a key role of R-loops in this process, exogenous RNase H1 expression reverses the synthetic lethality. Pharmacological suppression of cell-autonomous interferon responses or transcriptional silencing of cytosolic nucleic acid sensing PRR are also sufficient to abrogate ADAR1 dependency in BRCA1-mutant cells, in line with autocrine interferon poisoning playing a central part in this synthetic lethality. Our findings provide a preclinical rationale for assessing ADAR1-targeting agents in BRCA1/2-mutant cancers, and introduces a conceptually novel approach to synthetic lethal treatments, which exploits tumor cell-intrinsic cytosolic immunity as a targetable vulnerability of cancer cells.
ISSN:2041-1723

Similar Items