Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers PMID: 40730818

ADC Targets in Oncology

2026-04-10

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

1. The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France. [email protected].
2. Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France. [email protected].
3. The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. [email protected].
4. The Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. [email protected].
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. [email protected].
24. The Breast Cancer Now Toby Robins Breast Cancer Research Centre, London, UK. [email protected].
25. The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France. [email protected].
26. Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France. [email protected].
27. Drug Development Department (DITEP), Gustave Roussy, Villejuif, France. [email protected].
28. The University College of London Cancer Institute, University College of London, London, UK. [email protected].

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.