Mapping combinatorial drug effects to DNA damage response kinase inhibitors

Hanrui Zhang, Julian Kreis, Sven-Eric Schelhorn, Heike Dahmen, Thomas Grombacher, Michael Zühlsdorf, Frank T. Zenke and Yuanfang Guan ()
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Hanrui Zhang: University of Michigan
Julian Kreis: Merck Healthcare KGaA
Sven-Eric Schelhorn: Merck Healthcare KGaA
Heike Dahmen: Merck Healthcare KGaA
Thomas Grombacher: Merck Healthcare KGaA
Michael Zühlsdorf: Merck Healthcare KGaA
Frank T. Zenke: Merck Healthcare KGaA
Yuanfang Guan: University of Michigan

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-44108-y

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