A Second Escape Route: How Tumors Learn to Survive PARP Inhibitors

PARP inhibitors are among the greatest successes of precision oncology. In tumors with defective BRCA1 or BRCA2, one DNA repair route is already lost, while blocking PARP removes a second one. As a result, the cancer cell dies while healthy cells survive. The approach is now used in several carcinomas, including those of the ovary, breast, pancreas, and prostate. Its limit, however, is familiar to oncologists: resistance almost always develops, and the reasons behind it are only partly understood.

A study published on November 12, 2026, in Nature Communications addresses that gap. Researchers at the University of Oxford and the Vall d’Hebron Institute of Oncology treated BRCA1-deficient cancer cells and patient-derived xenografts with a PARP inhibitor until the tumors stopped responding, then examined what had changed. Alongside the expected loss of TP53BP1, they found something unexpected: resistant cells and tumors had switched on genes of the innate immune response, among them ISG15.

ISG15 turned out to be more than a marker. Blocking it restored drug sensitivity in resistant cells, while forcing cells to produce more of it made them resistant. The explanation lies in DNA replication: resistant cells need ISG15 to keep replication forks moving, to restart them when they stall, and to repair double-strand breaks by homologous recombination. In short, the tumor rebuilds the repair capacity that the treatment was designed to take away.

The evidence comes from cell and animal models, with no clinical validation yet, and it remains unclear whether the same mechanism operates in BRCA2-mutant tumors or across other cancer types. The direction, however, is clear. ISG15 and the enzymes that attach it to other proteins are druggable in principle, which makes combination with a PARP inhibitor a clinically testable idea — and whether it extends the time these drugs keep working is now an open and answerable question.

Source: Dagg RA, Paulsen T, Prasad B, et al. ISG15 promotes PARP inhibitor resistance in BRCA1-deficient cells by facilitating DNA replication and repair. Nature Communications 2026. DOI: 10.1038/s41467-026-78554-1 (open access)