Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers Journal Article
| Authors: | Chabanon, R. M.; Shcherbakova, L.; Lacroix-Triki, M.; Aglave, M.; Zeghondy, J.; Kriaa, V.; Gougé, A.; Garrido, M.; Edmond, E.; Bigot, L.; Krastev, D. B.; Brough, R.; Pettitt, S.; Thomas-Bonafos, T.; Samstein, R.; Massard, C.; Deloger, M.; Tutt, A. N.; Barlesi, F.; Loriot, Y.; Delaloge, S.; Tawk, M.; Degerny, C.; Lin, Y. L.; Pistilli, B.; Pasero, P.; Lord, C. J.; Postel-Vinay, S. |
| Article Title: | Autocrine interferon poisoning mediates ADAR1-dependent synthetic lethality in BRCA1/2-mutant cancers |
| 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. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | immunohistochemistry; controlled study; human tissue; protein phosphorylation; unclassified drug; human cell; genetics; mutation; interferon; nonhuman; neoplasm; neoplasms; cell proliferation; mouse; phenotype; animal; metabolism; animals; mice; cell viability; cell survival; animal experiment; animal model; protein; small interfering rna; in vivo study; in vitro study; enzyme activity; cell line, tumor; breast neoplasms; brca1 protein; brca2 protein; rna binding protein; rna; gene expression regulation; rna-binding proteins; gene expression regulation, neoplastic; immune response; gene interaction; breast tumor; tumor cell line; autocrine communication; endonuclease; brca1 protein, human; nucleic acid; ribonuclease; inhibition; dna rna hybridization; colony formation; synthetic lethality; interferon type i; pattern recognition; adenosine deaminase; rna editing; pattern recognition receptor; interferons; cancer; humans; human; male; female; article; rna sequencing; crispr-cas9 system; malignant neoplasm; short term survival; synthetic lethal mutations; retina pigment cell; cgas sting signaling; synthetic lethal mutation; adar protein, human; adar1 protein; autocrine signaling; sum149pt cell line |
| Journal Title: | Nature Communications |
| Volume: | 16 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2025-07-29 |
| Start Page: | 6972 |
| Language: | English |
| DOI: | 10.1038/s41467-025-62309-5 |
| PUBMED: | 40730818 |
| PROVIDER: | scopus |
| PMCID: | PMC12307730 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
