Abstract
In 2013, we published a comparative analysis mutation and gene expression profiles and drug sensitivity measurements for 15 drugs characterized in the 471 cancer cell lines screened in the Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE). While we found good concordance in gene expression profiles, there was substantial inconsistency in the drug responses reported by the GDSC and CCLE projects. We received extensive feedback on the comparisons that we performed. This feedback, along with the release of new data, prompted us to revisit our initial analysis. Here we present a new analysis using these expanded data in which we address the most significant suggestions for improvements on our published analysis - that targeted therapies and broad cytotoxic drugs should have been treated differently in assessing consistency, that consistency of both molecular profiles and drug sensitivity measurements should both be compared across cell lines, and that the software analysis tools we provided should have been easier to run, particularly as the GDSC and CCLE released additional data. Our re-analysis supports our previous finding that gene expression data are significantly more consistent than drug sensitivity measurements. The use of new statistics to assess data consistency allowed us to identify two broad effect drugs and three targeted drugs with moderate to good consistency in drug sensitivity data between GDSC and CCLE. For three other targeted drugs, there were not enough sensitive cell lines to assess the consistency of the pharmacological profiles. We found evidence of inconsistencies in pharmacological phenotypes for the remaining eight drugs. Overall, our findings suggest that the drug sensitivity data in GDSC and CCLE continue to present challenges for robust biomarker discovery. This re-analysis provides additional support for the argument that experimental standardization and validation of pharmacogenomic response will be necessary to advance the broad use of large pharmacogenomic screens.
Highlights
The goal of precision medicine is the identification of the best therapy for each patient and their own unique manifestation of a disease
In 2013 we reported inconsistency in the drug sensitivity phenotypes measured by the Genomics of Drug Sensitivity in Cancer (GDSC) and the Cancer Cell Lines Encyclopedia (CCLE) studies
This inconsistency can be clearly seen by plotting drug response reported for each of the 15 drugs provided in both GDSC and Cell Line Encyclopedia (CCLE) for the 471 cell lines assayed by both studies7–10
Summary
The goal of precision medicine is the identification of the best therapy for each patient and their own unique manifestation of a disease. The gene expression data showed reasonable consistency between the two studies, the drug sensitivity measurements were surprisingly inconsistent This inconsistency can be clearly seen by plotting drug response reported for each of the 15 drugs provided in both GDSC and CCLE for the 471 cell lines assayed by both studies. Since the publication of our comparative analysis, we received a great deal of constructive feedback from the scientific community regarding multiple aspects of the analysis we reported, including suggestions for analytical methods that might uncover greater consistency between the studies Both GDSC and CCLE have released new drug sensitivity and molecular profiling data, allowing us to revisit our initial analysis, and to extend it using these new data
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