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.
Highlights
Despite the current progress in the development of innovative anticancer therapeutics, the patient’s response to treatment remains largely individual, demanding identification of novel biomarkers predicting effectiveness of therapy for a patient
We for the first time compared molecular pathway activation features linked with the sensitivity of human cells to four target anticancer drugs routinely used for treatment of renal carcinoma and other cancers: Pazopanib, Sunitinib, Sorafenib and Temsirolimus
We compared pathway activation strength (PAS) signatures for experimental group of samples including eleven human cell lines grown and profiled in our laboratory, and for a database linked with “Genomics of Drug Sensitivity in Cancer” [6] project published on GDS website and including transcriptomes of 227 different human cell lines
Summary
Despite the current progress in the development of innovative anticancer therapeutics, the patient’s response to treatment remains largely individual, demanding identification of novel biomarkers predicting effectiveness of therapy for a patient. These markers may deal with specific genetic, epigenetic and gene expression features of cancer tissues [1]. A number of projects have been initiated to estimate the efficacy of therapeutic compounds on various cancer cell lines and link it to candidate genetic biomarkers. Comparison of pretreatment gene expression patterns with the activities of certain components may be a useful tool for the identification of novel biomarkers predicting response to a therapeutic, at least at the level of cell
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