PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications

• Published in: Molecular cancer Vol. 19; no. 1; pp. 49 - 15
• Main Authors: Zhu, Heng, Wei, Miaoyan, Xu, Jin, Hua, Jie, Liang, Chen, Meng, Qingcai, Zhang, Yiyin, Liu, Jiang, Zhang, Bo, Yu, Xianjun, Shi, Si
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 02-03-2020; BioMed Central; BMC
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Biological markers; Biotechnology; BRCA; BRCA mutations; Breast cancer; Cancer therapies; Cancer treatment; Carcinogenesis; Cell death; Chemotherapy; Chemotherapy resistance; Clinical trials; Deoxyribonucleic acid; Development and progression; Diseases; DNA; DNA damage; DNA repair; Drugs; Gene mutation; Genes; Genetic aspects; Genetic research; Genomes; Health risk assessment; Homologous recombination repair; Humans; Kinases; Medical prognosis; Metastasis; Molecular modelling; Monosaccharides; Mutation; Olaparib; Ovarian cancer; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PARP inhibitor; Polo; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prognosis; Proteins; Response rates; Review; Synthetic lethality; Talazoparib; Therapeutic applications; Tumors; Homologous recombination repair; BRCA; Chemotherapy resistance; Pancreatic cancer; PARP inhibitor; Biomarkers; Synthetic lethality
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-020-01167-9

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.