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<p>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 <i>BRCA1/2</i> and <i>ADAR1</i> are synthetically lethal, and that ADAR1 activity is upregulated in <i>BRCA1/2</i>-mutant cancers. ADAR1 depletion in <i>BRCA1</i>-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 <i>ADAR1</i> dependency in <i>BRCA1</i>-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 <i>BRCA1/2</i>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月29日

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

摘要

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.