Targeting DNA Replication Stress for Cancer Therapy
Abstract
:1. Introduction
1.1. Replication Stress and Its Underlying Mechanisms
1.2. Rationale for Enhancing Replication Stress to Cause Cancer Cell Death
2. Approaches to Harness Replication Stress for the Treatment of Cancer
2.1. Conventional Approaches
Radiation and chemotherapy
2.2. Emerging Approaches
2.2.1. Targeting ATR-Chk1 Signaling
2.2.2. PARP1 Inhibitors
2.2.3. Other Targets Including WEE1, MELK and Neddylation, etc.
3. Future Directions
3.1. Potential of Combination Therapy
3.2. Identification of Future Targets
3.3. Identification of Biomarkers to Detect and Track Replication Stress and Predict Treatment Response
3.4. Identification of Resistance Mechanisms
4. Conclusions
Acknowledgments
Conflicts of Interest
References
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Target/mechanism | Compounds | Stage of development | Reference |
---|---|---|---|
DNA misincorporation/modification | Alkylating agents e.g., cyclophosphamide, temozolamide, etc. | Approved | [20] |
Platinum compounds e.g., cisplatin, carboplatin, etc. | Approved | [21] | |
Ribonucleotide reductase | Gemcitabine | Approved | [24] |
Thymidylate synthetase | 5-fluorouracil | Approved | [25] |
Topoisomerase I | Irinotecan, topotecan | Approved | [29] |
Topoisomerase II | Etoposide, doxrubicin | Approved | [30] |
Chk1 | UCN-01 | Phase I/II. Multiple studies completed | [34,40] |
LY2606368 | Phase I/II, one study completed | [36] | |
AZD7762 | Phase I. One completed. | [41,42] | |
ATR | AZD6738 | Phase I, one study completed | [37] |
PARP1 | Olaparib and niraparib | Approved | [43,44,45] |
WEE1 | MK-1775 | Phase I | [46,47] |
MELK | OTS167 | Phase I, 2 studies | [48,49] |
NAE | MLN4924 | Phase I, multiple studies | [50] |
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Zhang, J.; Dai, Q.; Park, D.; Deng, X. Targeting DNA Replication Stress for Cancer Therapy. Genes 2016, 7, 51. https://doi.org/10.3390/genes7080051
Zhang J, Dai Q, Park D, Deng X. Targeting DNA Replication Stress for Cancer Therapy. Genes. 2016; 7(8):51. https://doi.org/10.3390/genes7080051
Chicago/Turabian StyleZhang, Jun, Qun Dai, Dongkyoo Park, and Xingming Deng. 2016. "Targeting DNA Replication Stress for Cancer Therapy" Genes 7, no. 8: 51. https://doi.org/10.3390/genes7080051
APA StyleZhang, J., Dai, Q., Park, D., & Deng, X. (2016). Targeting DNA Replication Stress for Cancer Therapy. Genes, 7(8), 51. https://doi.org/10.3390/genes7080051