PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications
Abstract Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) poly...
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Molecular Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12943-020-01167-9 |
| _version_ | 1819069334987735040 |
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| author | Heng Zhu Miaoyan Wei Jin Xu Jie Hua Chen Liang Qingcai Meng Yiyin Zhang Jiang Liu Bo Zhang Xianjun Yu Si Shi |
| author_facet | Heng Zhu Miaoyan Wei Jin Xu Jie Hua Chen Liang Qingcai Meng Yiyin Zhang Jiang Liu Bo Zhang Xianjun Yu Si Shi |
| author_sort | Heng Zhu |
| collection | DOAJ |
| description | Abstract Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer. |
| first_indexed | 2024-12-21T16:48:24Z |
| format | Article |
| id | doaj.art-a36f2a674c4c420e9fbf056ab660d4ba |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-21T16:48:24Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-a36f2a674c4c420e9fbf056ab660d4ba2022-12-21T18:56:56ZengBMCMolecular Cancer1476-45982020-03-0119111510.1186/s12943-020-01167-9PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applicationsHeng Zhu0Miaoyan Wei1Jin Xu2Jie Hua3Chen Liang4Qingcai Meng5Yiyin Zhang6Jiang Liu7Bo Zhang8Xianjun Yu9Si Shi10Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterDepartment of Pancreatic Surgery, Fudan University Shanghai Cancer CenterAbstract Pancreatic cancer is a highly lethal disease with a poor prognosis, and existing therapies offer only limited effectiveness. Mutation gene sequencing has shown several gene associations that may account for its carcinogenesis, revealing a promising research direction. Poly (ADP-ribose) polymerase (PARP) inhibitors target tumor cells with a homologous recombination repair (HRR) deficiency based on the concept of synthetic lethality. The most prominent target gene is BRCA, in which mutations were first identified in breast cancer and ovarian cancer. PARP inhibitors can trap the PARP-1 protein at a single-stranded break/DNA lesion and disrupt its catalytic cycle, ultimately leading to replication fork progression and consequent double-strand breaks. For tumor cells with BRCA mutations, HRR loss would result in cell death. Pancreatic cancer has also been reported to have a strong relationship with BRCA gene mutations, which indicates that pancreatic cancer patients may benefit from PARP inhibitors. Several clinical trials are being conducted and have begun to yield results. For example, the POLO (Pancreatic Cancer Olaparib Ongoing) trial has demonstrated that the median progression-free survival was observably longer in the olaparib group than in the placebo group. However, PARP inhibitor resistance has partially precluded their use in clinical applications, and the major mechanism underlying this resistance is the restoration of HRR. Therefore, determining how to use PARP inhibitors in more clinical applications and how to avoid adverse effects, as well as prognosis and treatment response biomarkers, require additional research. This review elaborates on future prospects for the application of PARP inhibitors in pancreatic cancer.http://link.springer.com/article/10.1186/s12943-020-01167-9PARP inhibitorPancreatic cancerBRCASynthetic lethalityHomologous recombination repairChemotherapy resistance |
| spellingShingle | Heng Zhu Miaoyan Wei Jin Xu Jie Hua Chen Liang Qingcai Meng Yiyin Zhang Jiang Liu Bo Zhang Xianjun Yu Si Shi PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications Molecular Cancer PARP inhibitor Pancreatic cancer BRCA Synthetic lethality Homologous recombination repair Chemotherapy resistance |
| title | PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications |
| title_full | PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications |
| title_fullStr | PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications |
| title_full_unstemmed | PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications |
| title_short | PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications |
| title_sort | parp inhibitors in pancreatic cancer molecular mechanisms and clinical applications |
| topic | PARP inhibitor Pancreatic cancer BRCA Synthetic lethality Homologous recombination repair Chemotherapy resistance |
| url | http://link.springer.com/article/10.1186/s12943-020-01167-9 |
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