Back to Search Start Over

Analysis of Compound Synergy in High-Throughput Cellular Screens by Population-Based Lifetime Modeling

Authors :
Martin Peifer
Jonathan Weiss
Martin L Sos
Mirjam Koker
Stefanie Heynck
Christian Netzer
Stefanie Fischer
Haridas Rode
Daniel Rauh
Jörg Rahnenführer
Roman K Thomas
Source :
PLoS ONE, PLoS ONE, Vol 5, Iss 1, p e8919 (2010)
Publication Year :
2010
Publisher :
Public Library of Science, 2010.

Abstract

Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor-shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhanced tumor control and prolonged survival. However, methods querying the efficacy of such combinations have been hampered by limited scalability, analytical resolution, statistical feasibility, or a combination thereof. We have developed a theoretical framework modeling cellular viability as a stochastic lifetime process to determine synergistic compound combinations from high-throughput cellular screens. We apply our method to data derived from chemical perturbations of 65 cancer cell lines with two inhibitors. Our analysis revealed synergy for the combination of both compounds in subsets of cell lines. By contrast, in cell lines in which inhibition of one of both targets was sufficient to induce cell death, no synergy was detected, compatible with the topology of the oncogenically activated signaling network. In summary, we provide a tool for the measurement of synergy strength for combination perturbation experiments that might help define pathway topologies and direct clinical trials.

Details

Language :
English
ISSN :
19326203
Volume :
5
Issue :
1
Database :
OpenAIRE
Journal :
PLoS ONE
Accession number :
edsair.pmid.dedup....b3af053f091ab0da9f0b3cbd98a1e8a9