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.

Synthesis of Novel Class of <i>N</i>-Alkyl-isatin-3-iminobenzoic Acid Derivatives and Their Biological Activity in Zebrafish Embryos and Human Cancer Cell Lines

“…The IC50 values of sunitinib has been reported as 6 µM 37) and 2.3 µM 38) in Jurkat cells, whereas the IC50 values of compound 3f was 7.8 µM in Jurkat cells in this study. The structural comparison between compound 3f and sunitinib revealed that the compound 3f is very much structurally related to sunitinib, as both of the compounds share fluorine as their moiety in isatin ring (Figure 10) which might be center for the functional activity of these two compounds.…”

Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data

“…Previous work has focussed on developing predictive models using drug-sensitivity data from cell lines373839. MiSL provides an alternate synthetic lethality-based approach to identify predictive biomarkers for targeted therapies.…”

Perspectives and Challenges in Molecular-Based Diagnostics and Personalized Treatment for Recurrent High-Grade Gliomas

“…The enclosed algorithm operates with the so-called Pathway Activation Strength value, which is a qualitative characteristic of pathway activity in a cancer sample. This approach was used to identify molecular features accounting for the tumor response to target drugs in cell-based models [69] and patients [70]. In glioblastoma, 59 abnormally regulated intracellular signaling pathways could be revealed by Oncofinder [71].…”