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PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications
- Source :
- Molecular Cancer, Molecular Cancer, Vol 19, Iss 1, Pp 1-15 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- 0301 basic medicine
Cancer Research
Synthetic lethality
BRCA
Poly (ADP-Ribose) Polymerase-1
Antineoplastic Agents
Review
Poly(ADP-ribose) Polymerase Inhibitors
Gene mutation
Biology
medicine.disease_cause
lcsh:RC254-282
Olaparib
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Breast cancer
Pancreatic cancer
medicine
Animals
Humans
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Pancreatic Neoplasms
PARP inhibitor
030104 developmental biology
Oncology
chemistry
030220 oncology & carcinogenesis
Homologous recombination repair
Cancer research
Molecular Medicine
Chemotherapy resistance
Carcinogenesis
Ovarian cancer
Biomarkers
Subjects
Details
- ISSN :
- 14764598
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer
- Accession number :
- edsair.doi.dedup.....256659188ac60514ed6851cb011a28d5