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ISG15 promotes PARP inhibitor resistance in BRCA1-deficient cells by facilitating DNA replication and repair [Methyl-seq]

ABSTRACT: The use of poly(ADP-ribose) polymerase inhibitors (PARPi) has proven largely successful in targeting BRCA1/2-mutated tumours. However, the emergence of PARPi-resistant disease can reduce the efficacy of this treatment, posing significant challenges in the clinic. Here, we use multiple models of BRCA1-/- cells and patient-derived xenografts (PDXs) that have been treated with PARPi until they no longer responded to the drug, to characterise genomic and transcriptomic alterations specific to PARPi resistance. We find that abrogation of TP53BP1 expression occurs spontaneously during prolonged PARPi treatment, alongside TP53BP1 genomic deletions and promoter methylation. Additionally, innate immune response genes, including ISG15 and factors of the ISGylation machinery are upregulated in PARPi-resistant cells and tumours. We demonstrate that ISG15 inhibition re-sensitises PARPi-resistant cells to the drug and, conversely, that ISG15 overexpression in BRCA1-/- cells promotes PARPi resistance. Mechanistically, BRCA1-/- PARPi-resistant cells rely on ISG15 for replication fork progression and restart of stalled forks and for DNA double-strand break (DSB) repair via homologous recombination (HR). Our results indicate that complex ISG15 interactions with DNA replication/repair factors can drive PARPi resistance in BRCA1-deficient cancer cells and that targeting ISG15 has the potential to overcome PARPi resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE308092 | GEO | 2026/08/18

REPOSITORIES: GEO

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Project description:Background: PARP inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. Methods: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. STAT3-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the TME of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the anti-tumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and PDX models of ovarian cancer. Results: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Markedly increased populations of pro-tumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes pro-tumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of pro-tumor macrophages and increases tumor-infiltrating T-cells upon PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of PD-1 blockade. Conclusions: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of pro-tumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonist and overcome PARPi resistance in ovarian cancer.

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ISG15 promotes PARP inhibitor resistance in BRCA1-deficient cells by facilitating DNA replication and repair [Methyl-seq]

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