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 () and Sophie Postel-Vinay ()
Additional contact information
Roman M. Chabanon: Gustave Roussy
Liudmila Shcherbakova: Gustave Roussy
Magali Lacroix-Triki: Gustave Roussy
Marine Aglave: Gustave Roussy
Jean Zeghondy: Gustave Roussy
Victor Kriaa: University Paris-Saclay
Antoine Gougé: Gustave Roussy
Marlène Garrido: Gustave Roussy
Elodie Edmond: Gustave Roussy
Ludovic Bigot: Gustave Roussy
Dragomir B. Krastev: The Institute of Cancer Research
Rachel Brough: The Institute of Cancer Research
Stephen J. Pettitt: The Institute of Cancer Research
Thibault Thomas-Bonafos: Gustave Roussy
Robert Samstein: Memorial Sloan Kettering Cancer Center
Christophe Massard: Gustave Roussy
Marc Deloger: Gustave Roussy
Andrew NJ Tutt: The Breast Cancer Now Toby Robins Breast Cancer Research Centre
Fabrice Barlesi: Gustave Roussy
Yohann Loriot: Gustave Roussy
Suzette Delaloge: Gustave Roussy
Marcel Tawk: University Paris-Saclay
Cindy Degerny: University Paris-Saclay
Yea-Lih Lin: Institut de Génétique Humaine
Barbara Pistilli: Gustave Roussy
Philippe Pasero: Institut de Génétique Humaine
Christopher J. Lord: The Institute of Cancer Research
Sophie Postel-Vinay: Gustave Roussy

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62309-5

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