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

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.