TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC
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. DN...
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| Language: | English |
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BMC
2025-02-01
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| Series: | Cell & Bioscience |
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| Online Access: | https://doi.org/10.1186/s13578-025-01350-9 |
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| author | Xiao-Mei Tang Min-Min Shi Jia-Cheng Wang Yi-Jin Gu Yu-Ting Dai Qin-Xin Yang Jia Liu Ling-Jie Ren Xin-Yun Liu Chun Yang Fang-Fang Ma Ji-Bing Liu Hong Yu Da Fu Yun-Feng Wang |
| author_facet | Xiao-Mei Tang Min-Min Shi Jia-Cheng Wang Yi-Jin Gu Yu-Ting Dai Qin-Xin Yang Jia Liu Ling-Jie Ren Xin-Yun Liu Chun Yang Fang-Fang Ma Ji-Bing Liu Hong Yu Da Fu Yun-Feng Wang |
| author_sort | Xiao-Mei Tang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-635ab80f70404509b01d47de7912976f |
| institution | Kabale University |
| issn | 2045-3701 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell & Bioscience |
| spelling | doaj-art-635ab80f70404509b01d47de7912976f2025-02-09T12:56:21ZengBMCCell & Bioscience2045-37012025-02-0115111810.1186/s13578-025-01350-9TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDACXiao-Mei Tang0Min-Min Shi1Jia-Cheng Wang2Yi-Jin Gu3Yu-Ting Dai4Qin-Xin Yang5Jia Liu6Ling-Jie Ren7Xin-Yun Liu8Chun Yang9Fang-Fang Ma10Ji-Bing Liu11Hong Yu12Da Fu13Yun-Feng Wang14Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineShanghai Pinghe SchoolDepartment of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineState Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong UniversityDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of Pathology, The Affiliated Taizhou Peoples Hospital of Nanjing Medical UniversityDepartment of Anesthesiology, The Affiliated Taizhou People’s Hospital of Nanjing Medical UniversityDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineInstitute of Oncology, Affiliated Tumor Hospital of Nantong UniversityDepartment of Pathology, The Affiliated Taizhou Peoples Hospital of Nanjing Medical UniversityDepartment of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of MedicineDepartment of General Surgery, Pudong New Area People’s HospitalAbstract 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.https://doi.org/10.1186/s13578-025-01350-9PDACTOPBP1OlaparibAZD6738 |
| spellingShingle | Xiao-Mei Tang Min-Min Shi Jia-Cheng Wang Yi-Jin Gu Yu-Ting Dai Qin-Xin Yang Jia Liu Ling-Jie Ren Xin-Yun Liu Chun Yang Fang-Fang Ma Ji-Bing Liu Hong Yu Da Fu Yun-Feng Wang TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC Cell & Bioscience PDAC TOPBP1 Olaparib AZD6738 |
| title | TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC |
| title_full | TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC |
| title_fullStr | TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC |
| title_full_unstemmed | TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC |
| title_short | TOPBP1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and AZD6738 in PDAC |
| title_sort | topbp1 as a potential predictive biomarker for enhanced combinatorial efficacy of olaparib and azd6738 in pdac |
| topic | PDAC TOPBP1 Olaparib AZD6738 |
| url | https://doi.org/10.1186/s13578-025-01350-9 |
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