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

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• ADAR1 (a dsRNA-editing enzyme) is crucial for preventing autoimmune responses by regulating interferon pathways.
• ADAR1 is a potential target in immuno-oncology, but predictive biomarkers for its inhibition are lacking.
• BRCA1/2 mutations are common in various cancers and impact DNA repair pathways.

Purpose of the Study:

• To investigate the relationship between ADAR1 and BRCA1/2 mutations in cancer.
• To identify predictive biomarkers for ADAR1 inhibition in immuno-oncology.
• To explore novel synthetic lethal strategies targeting cancer vulnerabilities.

Main Methods:

• In vitro and in vivo experiments were conducted to assess synthetic lethality.
• RNA editing activity, R-loop formation, and interferon responses were analyzed in BRCA1/2-mutant cells.
• The role of RNase H1, pattern recognition receptors (PRR), and interferon signaling was evaluated.

Main Results:

• BRCA1/2 mutations and ADAR1 exhibit synthetic lethality, with ADAR1 activity upregulated in BRCA1/2-mutant cancers.
• ADAR1 depletion in BRCA1-mutant cells increases R-loops, leading to enhanced cytosolic nucleic acid sensing and autocrine interferon poisoning.
• Reversal of synthetic lethality was observed with RNase H1 expression or suppression of interferon responses/PRR.

Conclusions:

• BRCA1/2-mutant cancers are dependent on ADAR1, presenting a targetable vulnerability.
• ADAR1 inhibition represents a promising therapeutic strategy for BRCA1/2-mutant cancers.
• Exploiting tumor cell-intrinsic cytosolic immunity offers a novel synthetic lethal approach.