Journal article
Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments
University of Copenhagen1
Department of Applied Mathematics and Computer Science, Technical University of Denmark2
Dynamical Systems, Department of Applied Mathematics and Computer Science, Technical University of Denmark3
University of New South Wales4
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark5
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark6
Bacterial Synthetic Biology, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark7
Signaling networks are nonlinear and complex, involving a large ensemble of dynamic interaction states that fluctuate in space and time. However, therapeutic strategies, such as combination chemotherapy, rarely consider the timing of drug perturbations. If we are to advance drug discovery for complex diseases, it will be essential to develop methods capable of identifying dynamic cellular responses to clinically relevant perturbations.
Here, we present a Bayesian dose-response framework and the screening of an oncological drug matrix, comprising 10,000 drug combinations in melanoma and pancreatic cancer cell lines, from which we predict sequentially effective drug combinations. Approximately 23% of the tested combinations showed high-confidence sequential effects (either synergistic or antagonistic), demonstrating that cellular perturbations of many drug combinations have temporal aspects, which are currently both underutilized and poorly understood.
Language: | English |
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Publisher: | Elsevier |
Year: | 2017 |
Pages: | 2784-2791 |
ISSN: | 22111247 |
Types: | Journal article |
DOI: | 10.1016/j.celrep.2017.08.095 |
ORCIDs: | 0000-0001-8675-6527 , 0000-0003-0420-4839 and Sommer, Morten Otto Alexander |
Antineoplastic Combined Chemotherapy Protocols Bayes Theorem Biology (General) Cell Count Cell Line, Tumor Cell Survival Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Drug Synergism Humans QH301-705.5 Reproducibility of Results Time Factors cancer chemotherapy sequential time-stagger