2. Academic Validation
  3. 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

  • Nat Commun. 2025 Jul 29;16(1):6972. doi: 10.1038/s41467-025-62309-5.
Roman M Chabanon 1 2 3 4,  Liudmila Shcherbakova 5 6,  Magali Lacroix-Triki 7 8,  Marine Aglave 9,  Jean Zeghondy 10,  Victor Kriaa 11,  Antoine Gougé 5 6,  Marlène Garrido 5 6,  Elodie Edmond 12,  Ludovic Bigot 13,  Dragomir B Krastev 14 15,  Rachel Brough 14 15,  Stephen J Pettitt 14 15,  Thibault Thomas-Bonafos 5 6 16,  Robert Samstein 17 18 19,  Christophe Massard 16,  Marc Deloger 9,  Andrew Nj Tutt 15 20,  Fabrice Barlesi 10,  Yohann Loriot 13 16,  Suzette Delaloge 10,  Marcel Tawk 11,  Cindy Degerny 11,  Yea-Lih Lin 21 22,  Barbara Pistilli 10,  Philippe Pasero 21 22,  Christopher J Lord 23 24,  Sophie Postel-Vinay 25 26 27 28
Affiliations

Affiliations

  • 1 The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France. roman.chabanon@gustaveroussy.fr.
  • 2 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France. roman.chabanon@gustaveroussy.fr.
  • 3 The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. roman.chabanon@gustaveroussy.fr.
  • 4 The Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. roman.chabanon@gustaveroussy.fr.
  • 5 The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France.
  • 6 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France.
  • 7 Molecular Characterization of Breast and Gynecological Cancers Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France.
  • 8 Department of Pathology, Gustave Roussy, Villejuif, France.
  • 9 Bioinformatics (BiGR) Platform, Gustave Roussy, Villejuif, France.
  • 10 Department of Medical Oncology, Gustave Roussy, Villejuif, France.
  • 11 Inserm Unit U1195, University Paris-Saclay, Le Kremlin Bicêtre, France.
  • 12 Experimental and Translational Pathology (PETRA) Platform, AMMICa Unit (CNRS Unit UMS3655, Inserm Unit US23), Gustave Roussy, Villejuif, France.
  • 13 Adaptive Resistance to Anti-Cancer Therapies Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France.
  • 14 The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK.
  • 15 The Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK.
  • 16 Drug Development Department (DITEP), Gustave Roussy, Villejuif, France.
  • 17 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, USA.
  • 18 Department of Radiation Oncology, Mount Sinai Hospital, New York, USA.
  • 19 Precision Immunology Institute at Icahn School of Medicine at Mount Sinai, New York, USA.
  • 20 The Breast Cancer Now Research Unit, Guy's Hospital Cancer Centre, King's College London, London, UK.
  • 21 The Ligue Contre Le Cancer Maintenance of Genome Integrity during DNA Replication Laboratory, CNRS Unit UMR9002, Institut de Génétique Humaine, Montpellier, France.
  • 22 Université de Montpellier, Montpellier, France.
  • 23 The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. chris.lord@icr.ac.uk.
  • 24 The Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. chris.lord@icr.ac.uk.
  • 25 The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France. sophie.postel-vinay@gustaveroussy.fr.
  • 26 Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France. sophie.postel-vinay@gustaveroussy.fr.
  • 27 Drug Development Department (DITEP), Gustave Roussy, Villejuif, France. sophie.postel-vinay@gustaveroussy.fr.
  • 28 The University College of London Cancer Institute, University College of London, London, UK. sophie.postel-vinay@gustaveroussy.fr.
PMID: 40730818 DOI: 10.1038/s41467-025-62309-5
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.

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