Li Peng, Ye Junjie, Yang Qian, Wang Ni, Li Chaoyi, Zou Xiaoxiao, Luo Hanyan, Pan Yi, Jiang Lingxi, Shen Baiyong, Tang Zaiming, Zhong Qing
Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai, China.
Shanghai Key Laboratory of Pancreatic Neoplasms Translational Medicine, Research Institute of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Commun. 2025 Aug 5;16(1):7209. doi: 10.1038/s41467-025-62295-8.
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.
BRCAness是一种同源重组修复（HRR）缺陷表型，类似于BRCA1/2缺失，导致包括胰腺癌在内的BRCA相关癌症对PARP抑制剂敏感。然而，如何在BRCA功能正常的肿瘤中诱导BRCAness仍不清楚。我们在人胰腺癌细胞和标本中鉴定出OFD1是BRCA1的正向调节因子，其过表达与不良预后相关。OFD1缺失会损害HRR，并与PARP抑制剂产生合成致死性。从机制上讲，OFD1在细胞质中与E2F4相互作用，以防止转录抑制因子DREAM复合物在BRCA1启动子处组装。靶向OFD1或破坏其与E2F4的相互作用会促进E2F4核转位和DREAM复合物形成，从而抑制BRCA1表达。在胰腺癌异种移植、自发和患者来源的异种移植模型以及其他BRCA相关癌症模型中，OFD1抑制与奥拉帕尼具有协同作用。这些发现揭示了BRCA1转录调控的机制，并突出了OFD1作为在BRCA功能正常的胰腺癌中诱导BRCAness的治疗靶点。
