109: Autocrine Interferon Poisoning: ADAR1–BRCA Synthetic Lethality

️ Episode 109: Autocrine Interferon Poisoning: ADAR1–BRCA Synthetic Lethality

In this episode of PaperCast Base by Base, we explore how loss of the RNA editor ADAR1 becomes lethal to BRCA1/2‑mutant cancer cells through a tumor‑cell‑autonomous interferon response, outlining a biomarker‑guided path to ADAR1‑targeted therapy.

Study Highlights:
A focused PRR siRNA screen and multiple orthogonal validations revealed a robust synthetic lethality between BRCA1/2 mutations and ADAR1 loss across isogenic human and mouse models, non‑isogenic TNBC lines, and zebrafish, with the cytoplasmic ADAR1p150 isoform and its deaminase activity required for survival. ADAR1 depletion elevated R‑loops, replication stress, γ‑H2AX foci, micronuclei, and apoptosis in BRCA‑deficient cells, while RNase H1 overexpression partially rescued DNA‑damage phenotypes and viability, implicating R‑loop burden as a trigger. The knockout activated cytosolic nucleic‑acid sensing pathways—RIG‑I, MDA5, LGP2, PKR, and cGAS—driving type I interferon and integrated‑stress responses; co‑silencing these sensors or inhibiting JAK/STAT signaling abrogated lethality, whereas exogenous interferons enhanced it. Patient data showed higher cytoplasmic ADAR1p150 expression and increased A‑to‑I RNA editing activity in BRCA‑mutant tumors and PDX models, indicating an ADAR1 dependency that is detectable in clinical specimens.

Conclusion:
These results establish a clinically actionable blueprint in which BRCA1/2 status predicts vulnerability to ADAR1 inhibition by exploiting autocrine interferon poisoning rather than DNA breaks, suggesting combinations and sequencing distinct from PARP inhibitor strategies.

Reference:
Autocrine interferon poisoning mediates ADAR1‑dependent synthetic lethality in BRCA1/2‑mutant cancers. Nature Communications. 2025;16:6972. https://doi.org/10.1038/s41467-025-62309-5

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
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ADAR1; BRCA1/2; synthetic lethality; interferon; R-loops

Chapters

• (00:00:14) - Synthetic lethality in cancer therapy
• (00:02:02) - Why BRCA mutations continue to cause cancer
• (00:03:38) - 8R1's role in breast cancer
• (00:09:42) - Why ADR1 selectively kills BRCA1 and BRC
• (00:15:09) - BRCA mutant cancer: new way to treat the disease
• (00:17:36) - Base by base science podcast