Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1-deficient breast cancer by repressing IRF3

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) inhibitors are a promising therapy for BRCA-deficient cancers, leveraging synthetic lethality.
• The efficacy of DNA damage drugs is influenced by DNA repair signaling and immune responses.

Purpose of the Study:

• To investigate the impact of PARP inhibitors on spliceosome function and innate immune signaling.
• To elucidate the role of BRCA1 in mediating resistance to PARP inhibitors.
• To explore combination strategies to enhance PARP inhibitor efficacy.

Main Methods:

• Functional proteomics to analyze protein interactions.
• Analysis of alternative splicing and double-stranded RNA (dsRNA) accumulation.
• In vivo studies of combination therapy.

Main Results:

• PARP inhibitors perturb spliceosome function by enhancing PARP1-SF3B1 interaction, leading to altered splicing and dsRNA accumulation.
• Accumulated dsRNA triggers innate immune responses via dsRNA antiviral mimicry.
• BRCA1 deficiency impairs innate immune signaling by downregulating IRF3, causing intrinsic resistance to PARP inhibitors.
• Polyinosinic-polycytidylic acid (poly(I:C)), a dsRNA analog, sensitizes PARP inhibitors by enhancing dsRNA signaling.

Conclusions:

• BRCA1 deficiency compromises tumor cell innate immune response, leading to intrinsic resistance to PARP inhibitors.
• Combination therapy with PARP inhibitors and poly(I:C) enhances antitumor efficacy in vivo.
• This study reveals a mechanism of resistance and a potential therapeutic strategy for BRCA-deficient cancers.