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

Peng Li, Junjie Ye, Qian Yang, Ni Wang, Chaoyi Li, Xiaoxiao Zou, Hanyan Luo, Yi Pan, Lingxi Jiang, Baiyong Shen (), Zaiming Tang () and Qing Zhong ()
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Peng Li: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Junjie Ye: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Qian Yang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Ni Wang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Chaoyi Li: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Xiaoxiao Zou: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Hanyan Luo: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Yi Pan: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Lingxi Jiang: Shanghai Jiao Tong University School of Medicine
Baiyong Shen: Shanghai Jiao Tong University School of Medicine
Zaiming Tang: Shanghai Jiao Tong University School of Medicine (SJTU-SM)
Qing Zhong: Shanghai Jiao Tong University School of Medicine (SJTU-SM)

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract BRCAness is a homologous recombination repair (HRR) deficiency phenotype mimicking BRCA1/2 loss, leading to PARP inhibitor sensitivity in BRCA-associated cancers including pancreatic cancer1–7. 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.

Date: 2025
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DOI: 10.1038/s41467-025-62295-8

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