Chabanon Roman M, Shcherbakova Liudmila, Lacroix-Triki Magali, Aglave Marine, Zeghondy Jean, Kriaa Victor, Gougé Antoine, Garrido Marlène, Edmond Elodie, Bigot Ludovic, Krastev Dragomir B, Brough Rachel, Pettitt Stephen J, Thomas-Bonafos Thibault, Samstein Robert, Massard Christophe, Deloger Marc, Tutt Andrew Nj, Barlesi Fabrice, Loriot Yohann, Delaloge Suzette, Tawk Marcel, Degerny Cindy, Lin Yea-Lih, Pistilli Barbara, Pasero Philippe, Lord Christopher J, Postel-Vinay Sophie
The ERC (Epi)Genetic Vulnerabilities in Solid Tumors and Sarcoma Laboratory, Inserm Unit UMR981, Gustave Roussy, Villejuif, France.
Faculté de Médecine, Université Paris-Saclay, Le Kremlin Bicêtre, France.
Nat Commun. 2025 Jul 29;16(1):6972. doi: 10.1038/s41467-025-62309-5.
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.
ADAR1是一种RNA编辑酶，它通过阻断胞质RNA传感器触发的干扰素反应来预防自身免疫，是免疫肿瘤学中的一个潜在靶点。然而，目前缺乏ADAR1抑制的预测性生物标志物。我们使用多种体外和体内系统表明，BRCA1/2与ADAR1存在合成致死性，并且ADAR1活性在BRCA1/2突变型癌症中上调。BRCA1突变细胞中ADAR1的缺失会导致R环增加，进而导致胞质核酸传感模式识别受体（PRR）上调，这些事件与肿瘤细胞自主的I型干扰素和综合应激反应相关。这最终会导致自分泌干扰素中毒。与R环在这一过程中的关键作用一致，外源性RNase H1的表达可逆转合成致死性。药理学抑制细胞自主的干扰素反应或胞质核酸传感PRR的转录沉默也足以消除BRCA1突变细胞对ADAR1的依赖性，这与自分泌干扰素中毒在这种合成致死性中起核心作用一致。我们的研究结果为评估BRCA1/2突变型癌症中靶向ADAR1的药物提供了临床前理论依据，并引入了一种概念上全新的合成致死治疗方法，该方法将肿瘤细胞内在的胞质免疫作为癌细胞的一个可靶向的脆弱点。
