Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma
Abstract Background There is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic th...
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2024-12-01
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| Online Access: | https://doi.org/10.1186/s12885-024-13334-y |
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| author | Thao D. Pham Jeffrey H. Becker Anastasia E. Metropulos Nida Mubin Christina Spaulding David J. Bentrem Hidayatullah G. Munshi |
| author_facet | Thao D. Pham Jeffrey H. Becker Anastasia E. Metropulos Nida Mubin Christina Spaulding David J. Bentrem Hidayatullah G. Munshi |
| author_sort | Thao D. Pham |
| collection | DOAJ |
| description | Abstract Background There is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic these defects in the absence of germline BRCA1/2 mutations are an area of active research in hopes of increasing the number of patients eligible for treatment with PARP inhibitors. The extent to which regorafenib, an FDA-approved tyrosine kinase inhibitor, can be used to enhance the efficacy of PARP inhibitors in PDAC cells without known BRCA1/2 mutations remains to be investigated. Methods Comet assay, cell cycle analysis, western blotting, and immunofluorescent detection of H2AXS139 were used to evaluate the extent to which regorafenib induces DNA damage in PDAC cell lines. The effects of regorafenib, either alone or in combination with PARPi inhibitors, on PDAC cell death were assessed by Annexin V/PI co-staining assay in cell lines and by immunohistochemistry staining for cleaved caspase-3 in mouse tumors and in ex vivo slice cultures of human PDAC tumors. Flow cytometry-based analysis was used to evaluate the ability of regorafenib to reprogram PDAC tumor microenvironment. Results We now show that regorafenib, a tyrosine-kinase inhibitor with efficacy in several gastrointestinal malignancies, can enhance the response of olaparib in pancreatic cancer. While regorafenib induces DNA damage and limits the ability of PDAC cells to resolve the damage, regorafenib by itself does not induce apoptosis. However, regorafenib in combination with olaparib further induces DNA damage in vitro, in tumor-bearing mice, and in ex vivo slice cultures of human PDAC tumors, resulting in increased apoptosis compared to olaparib alone. Notably, we show that the efficacy of the combination treatment is not dependent on cytolytic T cells. Conclusions Together, these findings demonstrate that regorafenib can attenuate DNA damage response and potentiate the efficacy of PARP inhibitors in PDAC tumors. |
| format | Article |
| id | doaj-art-08b826bd1e434751babc3447b927cdff |
| institution | DOAJ |
| issn | 1471-2407 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | BMC Cancer |
| spelling | doaj-art-08b826bd1e434751babc3447b927cdff2025-08-20T02:39:50ZengBMCBMC Cancer1471-24072024-12-0124111210.1186/s12885-024-13334-yRegorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinomaThao D. Pham0Jeffrey H. Becker1Anastasia E. Metropulos2Nida Mubin3Christina Spaulding4David J. Bentrem5Hidayatullah G. Munshi6Department of Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Medicine, Feinberg School of Medicine, Northwestern UniversityDepartment of Medicine, Feinberg School of Medicine, Northwestern UniversityJesse Brown VA Medical CenterDepartment of Medicine, Feinberg School of Medicine, Northwestern UniversityAbstract Background There is increasing interest in enhancing the response of the PARP inhibitor olaparib, which is currently approved for pancreatic ductal adenocarcinoma (PDAC) patients with defects in DNA damage repair associated with germline BRCA1/2 mutations. Moreover, agents that can mimic these defects in the absence of germline BRCA1/2 mutations are an area of active research in hopes of increasing the number of patients eligible for treatment with PARP inhibitors. The extent to which regorafenib, an FDA-approved tyrosine kinase inhibitor, can be used to enhance the efficacy of PARP inhibitors in PDAC cells without known BRCA1/2 mutations remains to be investigated. Methods Comet assay, cell cycle analysis, western blotting, and immunofluorescent detection of H2AXS139 were used to evaluate the extent to which regorafenib induces DNA damage in PDAC cell lines. The effects of regorafenib, either alone or in combination with PARPi inhibitors, on PDAC cell death were assessed by Annexin V/PI co-staining assay in cell lines and by immunohistochemistry staining for cleaved caspase-3 in mouse tumors and in ex vivo slice cultures of human PDAC tumors. Flow cytometry-based analysis was used to evaluate the ability of regorafenib to reprogram PDAC tumor microenvironment. Results We now show that regorafenib, a tyrosine-kinase inhibitor with efficacy in several gastrointestinal malignancies, can enhance the response of olaparib in pancreatic cancer. While regorafenib induces DNA damage and limits the ability of PDAC cells to resolve the damage, regorafenib by itself does not induce apoptosis. However, regorafenib in combination with olaparib further induces DNA damage in vitro, in tumor-bearing mice, and in ex vivo slice cultures of human PDAC tumors, resulting in increased apoptosis compared to olaparib alone. Notably, we show that the efficacy of the combination treatment is not dependent on cytolytic T cells. Conclusions Together, these findings demonstrate that regorafenib can attenuate DNA damage response and potentiate the efficacy of PARP inhibitors in PDAC tumors.https://doi.org/10.1186/s12885-024-13334-yPancreatic cancerRegorafenibDNA damageRad51OlaparibSyngeneic mouse model |
| spellingShingle | Thao D. Pham Jeffrey H. Becker Anastasia E. Metropulos Nida Mubin Christina Spaulding David J. Bentrem Hidayatullah G. Munshi Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma BMC Cancer Pancreatic cancer Regorafenib DNA damage Rad51 Olaparib Syngeneic mouse model |
| title | Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma |
| title_full | Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma |
| title_fullStr | Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma |
| title_full_unstemmed | Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma |
| title_short | Regorafenib induces DNA damage and enhances PARP inhibitor efficacy in pancreatic ductal carcinoma |
| title_sort | regorafenib induces dna damage and enhances parp inhibitor efficacy in pancreatic ductal carcinoma |
| topic | Pancreatic cancer Regorafenib DNA damage Rad51 Olaparib Syngeneic mouse model |
| url | https://doi.org/10.1186/s12885-024-13334-y |
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