Abstract
BackgroundThe NCI has undertaken a twenty-year project to characterize compound sensitivity patterns in a selected set of sixty tumor derived cell lines. Previous studies have explored the relationship between compound sensitivity patterns to gene expression, protein expression, and DNA copy number for these same cell lines. A strong correlation between the pattern of expression of a biomarker and sensitivity to a compound could suggest a clinically interesting biological relationship between the two.ResultsWe isolated RNA's and measured expression of 40000 genes using cDNA microarrays from the fifty-nine publicly available cell lines. Analysis of this data set in comparison with published gene expression data sets demonstrates a high degree of reproducibility in expression level measurements even using completely independent RNA preparations and array technologies. Using the fifty-nine cell lines for discovery and an additional seven cell lines for which extensive compound sensitivity data were available as a test set, we determined that gene-compound pairs with a correlation coefficient above 0.6 had a false discovery rate of approximately 5%. Large scale features of the gene expression and chemosensitivity data, such as tissue of origin and other physiological factors, did not seem to explain the majority of correlations between gene and compound patterns.ConclusionA comparison of gene expression and compound sensitivity in panels of cell lines was demonstrated to have a relatively high validation and low false discovery rate supporting the use of this approach and datasets for identifying candidate biomarkers and targeted biologically active compounds.
Highlights
The National Cancer Institute (NCI) has undertaken a twenty-year project to characterize compound sensitivity patterns in a selected set of sixty tumor derived cell lines
The US National Cancer Institute's (NCI) Developmental Therapeutics Program (DTP) screen for anticancer drugs has been a systematic attempt to explore the functional relationship between chemical compounds and toxicity in cell line cancer models, and was one of the first large scale public efforts to identify novel drugs for solid tumors
The DTP screen has made publicly available growth inhibition data on sixty tumor derived cell lines for tens of thousands of compounds. The coupling of this effort with a genomics perspective, in which the basal level of expression of genes on the NCI60 panel of cells was measured, introduced a novel approach for establishing a link between new therapies and biomarker candidates assessed by gene and protein expression patterns [4,5,6,7,8]
Summary
The NCI has undertaken a twenty-year project to characterize compound sensitivity patterns in a selected set of sixty tumor derived cell lines. The DTP screen has made publicly available growth inhibition data on sixty tumor derived cell lines (the NCI60) for tens of thousands of compounds The coupling of this effort with a genomics perspective, in which the basal level of expression of genes on the NCI60 panel of cells was measured, introduced a novel approach for establishing a link between new therapies and biomarker candidates assessed by gene and protein expression patterns [4,5,6,7,8]. This pharmcogenomics approach supposed that genes with patterns of expression across the cell lines which are highly correlated with compound sensitivity are candidate clinical biomarkers of drug efficacy, potentially even direct effectors of drug action, or targets for novel drug development with existing compound leads
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