2. Academic Validation
  3. TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC

TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC

  • Cell Biosci. 2025 Feb 7;15(1):17. doi: 10.1186/s13578-025-01350-9.
Xiao-Mei Tang 1 2 3,  Min-Min Shi 1 3,  Jia-Cheng Wang 4 5,  Yi-Jin Gu 6,  Yu-Ting Dai 7,  Qin-Xin Yang 1 8,  Jia Liu 1 3,  Ling-Jie Ren 1 3,  Xin-Yun Liu 8,  Chun Yang 9,  Fang-Fang Ma 1 3,  Ji-Bing Liu 2,  Hong Yu 10 11,  Da Fu 12 13 14,  Yun-Feng Wang 15
Affiliations

Affiliations

  • 1 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 2 Institute of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, Jiangsu, China.
  • 3 Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 4 Shanghai Pinghe School, Shanghai, 200127, China.
  • 5 Department of General Surgery, Pudong New Area People's Hospital, Shanghai, 201299, China.
  • 6 Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 7 State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, 200025, China.
  • 8 Department of Pathology, The Affiliated Taizhou Peoples Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, China.
  • 9 Department of Anesthesiology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, China.
  • 10 Department of Pathology, The Affiliated Taizhou Peoples Hospital of Nanjing Medical University, Taizhou, 225300, Jiangsu, China. yuhong@njmu.edu.cn.
  • 11 Department of Pathology, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, 225300, Jiangsu, China. yuhong@njmu.edu.cn.
  • 12 Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. fuda@shsmu.edu.cn.
  • 13 Institute of Oncology, Affiliated Tumor Hospital of Nantong University, Nantong, 226631, Jiangsu, China. fuda@shsmu.edu.cn.
  • 14 Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China. fuda@shsmu.edu.cn.
  • 15 Department of General Surgery, Pudong New Area People's Hospital, Shanghai, 201299, China. wangyunfeng197911@163.com.
PMID: 39920847 DOI: 10.1186/s13578-025-01350-9
Abstract

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.

Keywords

AZD6738; Olaparib; PDAC; TOPBP1.

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