Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.

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 query...

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Autores principales:	Martin Peifer, Jonathan Weiss, Martin L Sos, Mirjam Koker, Stefanie Heynck, Christian Netzer, Stefanie Fischer, Haridas Rode, Daniel Rauh, Jörg Rahnenführer, Roman K Thomas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d43d914520a846449df82e6532342907
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spelling	oai:doaj.org-article:d43d914520a846449df82e65323429072021-11-25T06:26:20ZAnalysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.1932-620310.1371/journal.pone.0008919https://doaj.org/article/d43d914520a846449df82e65323429072010-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20111714/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Despite 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.Martin PeiferJonathan WeissMartin L SosMirjam KokerStefanie HeynckChristian NetzerStefanie FischerHaridas RodeDaniel RauhJörg RahnenführerRoman K ThomasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 1, p e8919 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Martin Peifer Jonathan Weiss Martin L Sos Mirjam Koker Stefanie Heynck Christian Netzer Stefanie Fischer Haridas Rode Daniel Rauh Jörg Rahnenführer Roman K Thomas Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
description	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.
format	article
author	Martin Peifer Jonathan Weiss Martin L Sos Mirjam Koker Stefanie Heynck Christian Netzer Stefanie Fischer Haridas Rode Daniel Rauh Jörg Rahnenführer Roman K Thomas
author_facet	Martin Peifer Jonathan Weiss Martin L Sos Mirjam Koker Stefanie Heynck Christian Netzer Stefanie Fischer Haridas Rode Daniel Rauh Jörg Rahnenführer Roman K Thomas
author_sort	Martin Peifer
title	Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
title_short	Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
title_full	Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
title_fullStr	Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
title_full_unstemmed	Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
title_sort	analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/d43d914520a846449df82e6532342907
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Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.

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