Tang Xiao-Mei, Shi Min-Min, Wang Jia-Cheng, Gu Yi-Jin, Dai Yu-Ting, Yang Qin-Xin, Liu Jia, Ren Ling-Jie, Liu Xin-Yun, Yang Chun, Ma Fang-Fang, Liu Ji-Bing, Yu Hong, Fu Da, Wang Yun-Feng
Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
Institute of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, Jiangsu, China.
Cell Biosci. 2025 Feb 7;15(1):17. doi: 10.1186/s13578-025-01350-9.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and often lethal malignancy, requiring the development of enhanced therapeutic approaches. The DNA damage response (DDR) pathway is frequently altered during PDAC development, leading to an increased occurrence of DNA damage. DNA topoisomerase II-binding protein 1 (TOPBP1) plays a supportive role in regulating the DDR pathway, and its overexpression has been linked to the tumorigenesis of various cancers. This study investigated the biological role of TOPBP1 in PDAC pathogenesis and evaluated its clinical relevance in guiding treatment regimens. We examined the relationship between TOPBP1 expression, DDR pathway modulation, and therapeutic response in PDAC cell lines, primary cells, and subcutaneous mouse models. We found that elevated TOPBP1 expression was positively correlated with increased histologic grade and reduced patient survival in PDAC. TOPBP1 knockdown increased the sensitivity of PDAC cells to olaparib treatment and improved therapeutic efficacy in both PDAC cell lines and subcutaneous mouse models. Combination treatment with olaparib and AZD6738 effectively induced P53-dependent apoptosis via inhibiting the ATR pathway and enhancing signaling through the ATM pathway, which significantly reduced the viability of pancreatic cell lines. Notably, this combination therapy was more effective in PDAC cell lines exhibiting high TOPBP1 expression, indicating that TOPBP1 may serve as a useful predictive biomarker. In conclusion, TOPBP1 is a potential marker for optimizing the olaparib and AZD6738 combination therapy in PDAC. This study highlights the clinical significance of TOPBP1 in the treatment of PDAC and emphasizes the potential implications for a broader population of patients.
胰腺导管腺癌（PDAC）是一种极具侵袭性且往往致命的恶性肿瘤，需要开发更有效的治疗方法。在PDAC发展过程中，DNA损伤反应（DDR）途径经常发生改变，导致DNA损伤发生率增加。DNA拓扑异构酶II结合蛋白1（TOPBP1）在调节DDR途径中起辅助作用，其过表达与多种癌症的肿瘤发生有关。本研究调查了TOPBP1在PDAC发病机制中的生物学作用，并评估了其在指导治疗方案方面的临床相关性。我们研究了PDAC细胞系、原代细胞和皮下小鼠模型中TOPBP1表达、DDR途径调节与治疗反应之间的关系。我们发现，PDAC中TOPBP1表达升高与组织学分级增加和患者生存率降低呈正相关。敲低TOPBP1可提高PDAC细胞对奥拉帕尼治疗的敏感性，并改善PDAC细胞系和皮下小鼠模型中的治疗效果。奥拉帕尼和AZD6738联合治疗通过抑制ATR途径并增强ATM途径的信号传导，有效诱导了P53依赖性凋亡，这显著降低了胰腺细胞系的活力。值得注意的是，这种联合疗法在TOPBP1高表达的PDAC细胞系中更有效，表明TOPBP1可能是一种有用的预测生物标志物。总之，TOPBP1是优化PDAC中奥拉帕尼和AZD6738联合治疗的潜在标志物。本研究突出了TOPBP1在PDAC治疗中的临床意义，并强调了对更广泛患者群体的潜在影响。
