Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers
- 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
2025-07-29
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.