Enhancing reproducibility in cancer drug screening: how do we move forward?

Abstract

Large-scale pharmacogenomic high-throughput screening (HTS) studies hold great potential for generating robust genomic predictors of drug response. Two recent large-scale HTS studies have reported results of such screens, revealing several known and novel drug sensitivities and biomarkers. Subsequent evaluation, however, found only moderate interlaboratory concordance in the drug response phenotypes, possibly due to differences in the experimental protocols used in the two studies. This highlights the need for community-wide implementation of standardized assays for measuring drug response phenotypes so that the full potential of HTS is realized. We suggest that the path forward is to establish best practices and standardization of the critical steps in these assays through a collective effort to ensure that the data produced from large-scale screens would not only be of high intrastudy consistency, so that they could be replicated and compared successfully across multiple laboratories.

Figure 1

(A) Comparison of the Cancer Genome Project [4] and The Cancer Cell Line Encyclopedia [3] as published by Haibe-Kains et al. [5]. Our comparative study revealed a high degree of concordance between the gene- expression datasets, moderate concordance for the mutation data, but low concordance between drug-sensitivity assays; such inconsistency propagates into the gene–drug associations found by the two studies. (B) Main steps in the experimental protocols used in the CCLE and CGP studies; each step is further described in Supplementary Table 1. The choice of experimental procedures vastly differs between the two studies, illustrating the lack of standardization in large pharmacogenomic studies.