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Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs

Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to a...

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Autores principales: Venkova, Larisa, Aliper, Alexander, Suntsova, Maria, Kholodenko, Roman, Shepelin, Denis, Borisov, Nicolas, Malakhova, Galina, Vasilov, Raif, Roumiantsev, Sergey, Zhavoronkov, Alex, Buzdin, Anton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694985/
https://www.ncbi.nlm.nih.gov/pubmed/26317900
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author Venkova, Larisa
Aliper, Alexander
Suntsova, Maria
Kholodenko, Roman
Shepelin, Denis
Borisov, Nicolas
Malakhova, Galina
Vasilov, Raif
Roumiantsev, Sergey
Zhavoronkov, Alex
Buzdin, Anton
author_facet Venkova, Larisa
Aliper, Alexander
Suntsova, Maria
Kholodenko, Roman
Shepelin, Denis
Borisov, Nicolas
Malakhova, Galina
Vasilov, Raif
Roumiantsev, Sergey
Zhavoronkov, Alex
Buzdin, Anton
author_sort Venkova, Larisa
collection PubMed
description Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs and transcriptomes of various human cell lines. The microarray-based profiling of transcriptomes was performed for the cell lines before the addition of drugs to the medium, and experimental growth inhibition curves were built for each drug, featuring characteristic IC(50) values. We assayed here four target drugs - Pazopanib, Sorafenib, Sunitinib and Temsirolimus, and 238 different cell lines, of which 11 were profiled in our laboratory and 227 - in GDS project. Using the OncoFinder-processed transcriptomic data on ∼600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength (PAS) and IC(50) values for these drugs. Correlations reflect relationships between response to drug and pathway activation features. We intersected the results and found molecular pathways significantly correlated in both our assay and GDS project. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interactomic level.
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spelling pubmed-46949852016-01-20 Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs Venkova, Larisa Aliper, Alexander Suntsova, Maria Kholodenko, Roman Shepelin, Denis Borisov, Nicolas Malakhova, Galina Vasilov, Raif Roumiantsev, Sergey Zhavoronkov, Alex Buzdin, Anton Oncotarget Research Paper Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs. In this study, we compared the experimental data obtained in our laboratory and in the Genomics of Drug Sensitivity in Cancer (GDS) project for testing response to anticancer drugs and transcriptomes of various human cell lines. The microarray-based profiling of transcriptomes was performed for the cell lines before the addition of drugs to the medium, and experimental growth inhibition curves were built for each drug, featuring characteristic IC(50) values. We assayed here four target drugs - Pazopanib, Sorafenib, Sunitinib and Temsirolimus, and 238 different cell lines, of which 11 were profiled in our laboratory and 227 - in GDS project. Using the OncoFinder-processed transcriptomic data on ∼600 molecular pathways, we identified pathways showing significant correlation between pathway activation strength (PAS) and IC(50) values for these drugs. Correlations reflect relationships between response to drug and pathway activation features. We intersected the results and found molecular pathways significantly correlated in both our assay and GDS project. For most of these pathways, we generated molecular models of their interaction with known molecular target(s) of the respective drugs. For the first time, our study uncovered mechanisms underlying cancer cell response to drugs at the high-throughput molecular interactomic level. Impact Journals LLC 2015-07-30 /pmc/articles/PMC4694985/ /pubmed/26317900 Text en Copyright: © 2015 Venkova et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Venkova, Larisa
Aliper, Alexander
Suntsova, Maria
Kholodenko, Roman
Shepelin, Denis
Borisov, Nicolas
Malakhova, Galina
Vasilov, Raif
Roumiantsev, Sergey
Zhavoronkov, Alex
Buzdin, Anton
Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title_full Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title_fullStr Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title_full_unstemmed Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title_short Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
title_sort combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694985/
https://www.ncbi.nlm.nih.gov/pubmed/26317900
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