Journal Article

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

Degerny, Cindy, Chabanon, Roman M., Lacroix-Triki, Magali, Deloger, Marc, Shcherbakova, Liudmila, Pistilli, Barbara, Pettitt, Stephen J., Lord, Christopher J., Zeghondy, Jean, Krastev, Dragomir B., Brough, Rachel, Lin, Yea-Lih, Pasero, Philippe, Postel-Vinay, Sophie, Delaloge, Suzette, Aglave, Marine, Garrido, Marlène, Samstein, Robert, Edmond, Elodie, Thomas-Bonafos, Thibault, Tutt, Andrew NJ, Loriot, Yohann, Barlesi, Fabrice, Massard, Christophe, Bigot, Ludovic, Kriaa, Victor, Gougé, Antoine, Tawk, Marcel

2025

Overview

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. The RNA editing enzyme ADAR1 blocks interferon responses triggered by cytosolic RNA sensors, and has been proposed as a potential target in immuno-oncology. Here, the authors report that BRCA1/2 and ADAR1 are synthetic lethal, showing that ADAR1 depletion in BRCA1 -mutant cells causes autocrine interferon poisoning

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 13/89 / 14/19 / 38/91 / 42/70 / 45/88 / 631/208/191 / 631/250/262/2106 / 631/337/1427 / 631/337/1645/1944 / 64/116 / 692/4028/67/1857 / 82/80 / 96/1 / 96/106 / 96/109 / Adenosine Deaminase - genetics / Adenosine Deaminase - metabolism / Animals / Autocrine Communication / Autocrine signalling / Autoimmunity / Biomarkers / BRCA1 protein / BRCA1 Protein - genetics / BRCA1 Protein - metabolism / BRCA2 Protein - genetics / BRCA2 Protein - metabolism / Breast cancer / Breast Neoplasms - genetics / Cancer / Cancer immunotherapy / Cell Line, Tumor / Cells / Cellular stress response / CRISPR / Depletion / DNA damage / Editing / Experiments / Female / Gene Expression Regulation, Neoplastic / Gene silencing / Humanities and Social Sciences / Humans / Interferon / Interferon Type I - metabolism / Interferons - metabolism / Lethality / Life Sciences / Mice / multidisciplinary / Mutants / Mutation / Neoplasms - genetics / Nucleic acids / Oncology / Pattern recognition / Pattern recognition receptors / Poisoning / R-loops / Ribonuclease H1 / Ribonucleic acid / RNA / RNA editing / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / Sensors / Synthetic Lethal Mutations / Tumors