OFD1 inhibition induces BRCAness to create a therapeutic vulnerability to PARP inhibition in pancreatic cancer.

BRCAness is a homologous recombination repair (HRR) deficiency phenotype mimicking BRCA1/2 loss, leading to PARP inhibitor sensitivity in BRCA-associated cancers including pancreatic cancer. However, how to induce BRCAness in BRCA-proficient tumors remains unclear. We identify OFD1 as a positive regulator of BRCA1 in human pancreatic cancer cells and specimens, with its overexpression correlating with poor prognosis. OFD1 depletion impairs HRR and confers synthetic lethality with PARP inhibitors. Mechanistically, OFD1 interacts with E2F4 in the cytosol to prevent assembly of the transcriptional repressor DREAM complex at the BRCA1 promoter. Targeting OFD1 or disrupting its interaction with E2F4 promotes E2F4 nuclear translocation and DREAM complex formation, suppressing BRCA1 expression. OFD1 inhibition synergizes with olaparib in pancreatic cancer xenograft, spontaneous, and patient-derived xenograft models, and in other BRCA-associated cancer models. These findings reveal a mechanism of BRCA1 transcriptional regulation and highlight OFD1 as a therapeutic target to induce BRCAness in BRCA-proficient pancreatic cancer.