title: Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs.
abstract: 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 IC50 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 IC50 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.
authors: Drug Research and Design Department, Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Department of Personalized Medicine, First Oncology Research and Advisory Center, Moscow, Russia.
authors: Larisa
authors: L
authors: Venkova
authors: Drug Research and Design Department, Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Alexander
authors: A
authors: Aliper
authors: Drug Research and Design Department, Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Department of Personalized Medicine, First Oncology Research and Advisory Center, Moscow, Russia.|Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Maria
authors: M
authors: Suntsova
authors: Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors: Roman
authors: R
authors: Kholodenko
authors: Drug Research and Design Department, Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors: Denis
authors: D
authors: Shepelin
authors: Drug Research and Design Department, Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Department of Personalized Medicine, First Oncology Research and Advisory Center, Moscow, Russia.
authors: Nicolas
authors: N
authors: Borisov
authors: Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors: Galina
authors: G
authors: Malakhova
authors: National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors: Raif
authors: R
authors: Vasilov
authors: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Pirogov Russian National Research Medical University, Department of Oncology, Hematology and Radiotherapy, Moscow, Russia.|Moscow Institute of Physics and Technology, Department of Translational and Regenerative Medicine, Dolgoprudny, Moscow Region, Russia.
authors: Sergey
authors: S
authors: Roumiantsev
authors: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
authors: Alex
authors: A
authors: Zhavoronkov
authors: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|Group for Genomic Regulation of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.|National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors: Anton
authors: A
authors: Buzdin
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000737:chemistry; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D020123:Sirolimus / Q000031:analogs & derivatives / Q000737:chemistry; D000077157:Sorafenib; D013449:Sulfonamides / Q000737:chemistry; D000077210:Sunitinib; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D009536:Niacinamide; C401859:temsirolimus; C516667:pazopanib; D000077157:Sorafenib; D000077210:Sunitinib; D020123:Sirolimus
keywords: anticancer target drugs; cancer; gene expression; metabolic pathway; signaling pathway