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Cell Rep. 2017 Sep 19;20(12):2784-2791. doi: 10.1016/j.celrep.2017.08.095.

Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments.

Author information

1
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
2
DTU Compute, Technical University of Denmark, Kgs. Lyngby 2800, Denmark.
3
The Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Faculty of Medicine, University of New South Wales, Sydney, NSW 2010, Australia.
4
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby 2800, Denmark.
5
Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kgs. Lyngby 2800, Denmark.
6
Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark. Electronic address: linding@lindinglab.org.

Abstract

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.

KEYWORDS:

cancer; chemotherapy; sequential; time-stagger

PMID:
28930675
DOI:
10.1016/j.celrep.2017.08.095
[Indexed for MEDLINE]
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