Mapping combinatorial drug effects to DNA damage response kinase inhibitors.
Hanrui ZhangJulian KreisSven-Eric SchelhornHeike DahmenThomas GrombacherMichael ZühlsdorfFrank T ZenkeYuanfang GuanPublished in: Nature communications (2023)
One 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.
Keyphrases
- dna damage response
- dna repair
- dna damage
- cell cycle
- circulating tumor
- oxidative stress
- cell free
- single molecule
- cell proliferation
- early stage
- high resolution
- gene expression
- locally advanced
- endoplasmic reticulum stress
- squamous cell carcinoma
- papillary thyroid
- radiation therapy
- emergency department
- nucleic acid
- cell death
- mass spectrometry
- cell cycle arrest
- lymph node metastasis
- protein kinase
- signaling pathway
- replacement therapy