Unearthing new genomic markers of drug response by improved measurement of discriminative power

Cuong C. Dang, Antonio Peón, Pedro J. Ballester

Oncology drugs are only effective in a small proportion of cancer patients. Our current ability to identify these responsive patients before treatment is still poor in most cases. Thus, there is a pressing need to discover response markers for marketed and research oncology drugs. Screening these drugs against a large panel of cancer cell lines has led to the discovery of new genomic markers of in vitro drug response. However, while the identification of such markers among thousands of candidate drug-gene associations in the data is error-prone, an appraisal of the effectiveness of such detection task is currently lacking. Here we present a new non-parametric method to measuring the discriminative power of a drug-gene association. Unlike parametric statistical tests, the adopted non-parametric test has the advantage of not making strong assumptions about the data distorting the identification of genomic markers. Furthermore, we introduce a new benchmark to further validate these markers in vitro using more recent data not used to identify the markers. The application of this new methodology has led to the identification of 128 new genomic markers distributed across 61% of the analysed drugs, including 5 drugs without previously known markers, which were missed by the MANOVA test initially applied to analyse data from the Genomics of Drug Sensitivity in Cancer consortium. Discovering markers using more than one statistical test and testing them on independent data is unusual. We found this helpful to discard statistically significant drug-gene associations that were actually spurious correlations. This approach also revealed new, independently validated, in vitro markers of drug response such as Temsirolimus-CDKN2A (resistance) and Gemcitabine-EWS_FLI1 (sensitivity).