Breast cancer is the most common malignancy among women worldwide. About 10% of breast cancers are hereditary, and approximately 60% of these cases carry BRCA1 or BRCA2 mutations. Individuals harboring BRCA1 mutations exhibit a markedly increased risk of developing breast cancer. BRCA1 plays a critical role in maintaining genomic stability by repairing DNA double strand breaks (DSBs) through homologous recombination (HR). HR is a high-fidelity repair pathway, whereas non-homologous end joining (NHEJ) and microhomology mediated end joining (MMEJ) are error-prone, often leading to chromosomal aberrations and tumorigenesis. Based on the dependency of BRCA-deficient cells on alternative DNA repair pathways, poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed as targeted therapies. PARPi blocks PARP1 mediated single strand break repair pathways, inducing synthetic lethality in HR-deficient cells. Olaparib, the first approved PARPi, is now widely used for BRCA-mutated breast cancer and other HR deficient tumors. However, intrinsic resistance to PARPi has emerged as a major clinical challenge, necessitating mechanistic insights and novel combination strategies.
Recent studies indicate that DNA damage not only compromises genomic integrity but also activates innate immune responses. Cytosolic DNA fragments can trigger the cGAS-STING pathway, leading to interferon production and enhanced antitumor immunity. STING agonists combined with PARPi have shown synergistic effects. Moreover, DNA damage can cause the accumulation of double strand RNA (dsRNA), activating MAVS mediated antiviral mimicry responses. However, the underlying mechanisms remain poorly understood.
A recent study by Chuxia Deng and Edwin Cheung’s team at the University of Macau, published in Protein & Cell under the title “Tumor cell intrinsic dsRNA innate immune response triggered by PARP inhibitor is compromised in BRCA1 deficient breast cancer by repressing IRF3”, provides critical insights into this process. Using functional proteomics, the authors discovered that PARPi enhances the interaction between PARP1 and the spliceosome core factor SF3B1, thereby disrupting spliceosome function. This disruption leads to alternative spliced mRNA and dsRNA accumulation, which in turn activates an antiviral mimicry innate immune response. Importantly, the study uncovered a novel role of BRCA1. It regulates innate immune signaling through IRF3. BRCA1 deficiency results in IRF3 downregulation, dampening PARPi induced immune activation and reducing drug sensitivity, thereby conferring intrinsic resistance in BRCA1 deficient breast cancer cells. Notably, the dsRNA analog poly(I:C) further amplifies this immune signaling and significantly enhances PARPi sensitivity. Combined treatment with PARPi and poly(I:C) markedly improved antitumor efficacy in vivo.
In summary, this study reveals that BRCA1 deficiency impairs tumor cell intrinsic innate immune responses, driving PARPi resistance, a vulnerability that can be overcome by combining poly(I:C).
DOI：10.1093/procel/pwaf104