Abstract
AbstractOne fundamental principle that underlies various cancer treatments, such as traditional chemotherapy and radiotherapy, involves the induction of catastrophic DNA damage, leading to the apoptosis of cancer cells. In our study, we conduct a comprehensive dose-response combination screening focused on inhibitors that target key kinases involved in the DNA damage response (DDR): ATR, ATM, and DNA-PK. This screening involves 87 anti-cancer agents, including six DDR inhibitors, and encompasses 62 different cell lines spanning 12 types of tumors, resulting in a total of 17,912 combination treatment experiments. Within these combinations, we analyze the most effective and synergistic drug pairs across all tested cell lines, considering the variations among cancers originating from different tissues. Our analysis reveals inhibitors of five DDR-related pathways (DNA topoisomerase, PLK1 kinase, p53-inducible ribonucleotide reductase, PARP, and cell cycle checkpoint proteins) that exhibit strong combinatorial efficacy and synergy when used alongside ATM/ATR/DNA-PK inhibitors.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference65 articles.
1. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
2. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
3. Cohen, S. M. & Lippard, S. J. Cisplatin: from DNA damage to cancer chemotherapy. Prog. Nucleic Acid Res. Mol. Biol. 67, 93–130 (2001).
4. Baskar, R., Lee, K. A., Yeo, R. & Yeoh, K.-W. Cancer and radiation therapy: current advances and future directions. Int. J. Med. Sci. 9, 193–199 (2012).
5. Kelley, M. R. & Fishel, M. L. DNA Repair in Cancer Therapy: Molecular Targets and Clinical Applications (Academic Press, 2016).