Related Experiment Video
Updated: Jul 1, 2026
Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency
Published on: February 2, 2024
DNA damage response inhibitors in pancreatic cancer: progress and challenges
Yeyao Wu1, Wei Li1, Mengyun Wu1
1Radiology Laboratory, Department of Occupational Health and Radiological Health, Chongqing Center for Disease Control and Prevention, Chongqing, China.
Abstract:
Pancreatic cancer is one of the most lethal malignancies, with very limited treatment options beyond standard chemotherapy. The discovery of homologous recombination repair (HRR) deficiencies-such as BRCA1/2 and PALB2 mutations-has revealed a targetable vulnerability through the DNA damage response (DDR) pathway. This review systematically summarizes the application and current clinical landscape of DDR-targeted therapies in pancreatic cancer. We first discuss how DDR inhibitors have successfully translated from research into clinical practice as a targeted treatment option for pancreatic cancer patients. However, single-agent DDR inhibitors face major limitations, including a narrow beneficiary population, primary and acquired resistance, and dose-limiting toxicities. The central theme of this review is the paradigm shift from monotherapy to rational combination strategies. We therefore focus on emerging combination approaches, such as the PAD/PADtal triple regimen, dual-target inhibitors, sequential scheduling, combinations with immunotherapy, combinations with KRAS inhibitors, and novel targets (PRMT5, PARG, HuR). These strategies aim to overcome resistance, extend benefits beyond BRCA-mutant patients, and remodel the tumor immune microenvironment. Finally, we summarize current challenges-including limited accessibility, resistance mechanisms, and toxicities-and outline future directions, such as novel biomarkers, liquid biopsy for real-time resistance monitoring, and innovative adaptive trial designs. This review highlights the evolution of DDR-targeted therapy in pancreatic cancer toward personalized, combination-based precision medicine.
Insights
Targeting DNA damage response (DDR) pathways offers new pancreatic cancer treatments. Combination therapies show promise for overcoming resistance and expanding treatment benefits beyond specific mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pancreatic cancer is a highly lethal malignancy with limited therapeutic options.
- Homologous recombination repair (HRR) deficiencies (e.g., BRCA1/2, PALB2 mutations) represent a targetable vulnerability via the DNA damage response (DDR) pathway.
Purpose of the Study:
- To systematically review the clinical application and landscape of DDR-targeted therapies in pancreatic cancer.
- To highlight the shift from monotherapy to rational combination strategies for improved efficacy and broader patient benefit.
Main Methods:
- Systematic review of current literature on DDR inhibitors in pancreatic cancer.
- Analysis of emerging combination strategies including triple regimens, dual-target inhibitors, and combinations with immunotherapy or KRAS inhibitors.
- Discussion of novel targets and future directions in DDR-targeted therapy.
Main Results:
- DDR inhibitors have entered clinical practice but face limitations like narrow patient populations and resistance.
- Combination strategies are emerging to overcome resistance, extend benefits to non-BRCA mutant patients, and modulate the tumor immune microenvironment.
- Novel targets (PRMT5, PARG, HuR) and approaches like liquid biopsies are under investigation.
Conclusions:
- The evolution of DDR-targeted therapy in pancreatic cancer is moving towards personalized, combination-based precision medicine.
- Future directions include identifying new biomarkers, utilizing liquid biopsies for resistance monitoring, and employing adaptive trial designs.
