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Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics

Nature Biotechnology volume 35, pages 500–502 (2017)Cite this article

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A recently released data set from the Genentech Cell Line Screening Initiative (gCSI)7 is unique among large-scale drug response data sets in reporting cell division times, which are required for GR calculations. Median cell line division times varied about twofold across tissue types and up to threefold within cell lines of a given type (note that division times also vary with culture conditions1,2). Lymphoid cancer lines had the shortest median division times at 29 h with an interquartile range (IQR) of 15 h, whereas breast cancer lines had the longest division times at 53 h (IQR = 16 h; Fig. 1b). All other things being equal, slower division rates increase IC50 and Emax values for simple arithmetic reasons (Fig. 1a)1. In the gCSI data set, both IC50 and Emax were in fact substantially higher for the slowest dividing cell types relative to the fastest (Spearman's r > 0.61, P < 0.005). For drugs such as paclitaxel (Abraxane, Taxol), docetaxel (Taxotere), and gemcitabine (Gemzar), drug sensitivity also correlated with cell division times (r > 0.35, P < 5.6 × 10−13 for IC50; r > 0.4, P < 1.4 × 10−16 for Emax). On the basis of IC50 values, bone cancer cells were reportedly 60-fold more drug sensitive on average than breast cancer cells even though the drugs in the gCSI data set are primarily used to treat the latter disease. By contrast, we found that median GR50 and GRmax values are not significantly correlated across fast- and slow-growing tumor cell types (P > 0.20). Thus, the correlation between tumor type and median IC50 or Emax values arises from systematic variation in division time.

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Figure 1: Division rate confounds IC50 values and pharmacogenomic associations.
Figure 2: Variation in efficacy and genomic enrichment based on GRmax values in the gCSI data set.

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Authors and Affiliations

  1. Department of Systems Biology, HMS LINCS Center, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Marc Hafner, Mario Niepel & Peter K Sorger

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  1. Marc Hafner
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  2. Mario Niepel
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Correspondence to Peter K Sorger.

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Integrated supplementary information

Supplementary Figure 1 Effect of division time (Td) on conventional and GR metrics.

(a) Simulation of responses to two drugs inducing either partial growth inhibition (blue) or cell death (green) in slow- and fast-growing cell lines for a 72 h assay. Colored lines correspond to the cell count over time for the maximal drug effect; black lines correspond to untreated control samples; x0 is the cell count at the time of treatment; xctrl and x(c) are the cell counts in the untreated and treated samples at the end of treatment. End-point ratios (x(c)/xctrl) are reported. (b) Simulation of the effects of a hypothetical mutation on cell division time (by row) and drug sensitivity (by column) in comparison to a reference response (center plot in gray). The untreated population is shown in black and the treated population in color based on the type of response (partial growth inhibition in blue, cytostasis in red, or cell death in green). End-point relative cell counts are reported. (c) Conventional (top) and GR-based (bottom) drug dose-response curves corresponding to the conditions in (b). Equations for each method is based on the values defined in (a). Note that the GR curves for each type of response overlap. (d) Conventional and GR-based sensitivity metrics corresponding to the dose-response curves in (c).

Supplementary Figure 2 GR metrics for the gCSI dataset.

Each panel shows GRmax plotted against GR50 values across all cell lines for a given drug. For illustration purposes, GR50 values are capped at 31 μM.

Supplementary Figure 3 GR metrics and entropies for the CTRP dataset.

(a) Entropies for GR50 and GR2μM for each drug in the CTRP dataset. Size of the circle reflects the mutual information between GR50 and GR2μM. (b) Joint entropy of GR50 and GR2μM (H50+2μM) metrics plotted against the entropy of the GRAOC value (HAOC). (c) Distribution of entropies for GR50 (H50), GR2μM (H2μM), GRAOC (HAOC), and joint entropy of GR50 and GR2μM (H50+2μM). Red line marks the median value. (d) Each panel shows GR2μM plotted against GR50 values across all cell lines for drugs or drug combinations with the highest joint entropy of GR50 and GR2μM (H50+2μM). For illustration purposes GR50 values are capped at 31 μM.

Supplementary Figure 4 Correlation between the gCSI and CTRP datasets.

(a) Spearman's correlation values between the two datasets based on conventional AUC (x-axis) or GRAOC (y-axis) for the nine drugs shared between the datasets. Mean increase in correlation and p-value of a t-test are reported. Note that gemcitabine (blue cross) is not included in the statistics because it was used for calibration. (b) Each pair of panels shows the AUC (left) or GRAOC (right) values calculated on the CTRP dataset versus the values on the gCSI dataset for all cell lines for each drug shared between the datasets. Each pair of plots is a different drug; Spearman's correlation is displayed at the top of each plot.

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Hafner, M., Niepel, M. & Sorger, P. Alternative drug sensitivity metrics improve preclinical cancer pharmacogenomics. Nat Biotechnol 35, 500–502 (2017). https://doi.org/10.1038/nbt.3882

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