Drug GRADE: An Integrated Analysis of Population Growth and Cell Death Reveals Drug-Specific and Cancer Subtype-Specific Response Profiles

SUMMARY

When evaluating anti-cancer drugs, two different measurements are used: relative viability, which scores an amalgam of proliferative arrest and cell death, and fractional viability, which specifically scores the degree of cell killing. We quantify relationships between drug-induced growth inhibition and cell death by counting live and dead cells using quantitative microscopy. We find that most drugs affect both proliferation and death, but in different proportions and with different relative timing. This causes a non-uniform relationship between relative and fractional response measurements. To unify these measurements, we created a data visualization and analysis platform called drug GRADE, which characterizes the degree to which death contributes to an observed drug response. GRADE captures drug- and genotype-specific responses, which are not captured using traditional pharmacometrics. This study highlights the idiosyncratic nature of drug-induced proliferative arrest and cell death. Furthermore, we provide a metric for quantitatively evaluating the relationship between these behaviors.

In Brief

Anti-cancer drugs affect both the growth and survival of cancer cells. Commonly used measures of drug sensitivity do not distinguish between these two different outcomes. Schwartz et al. developed GRADE, a drug analysis method that reveals the proportional contributions of cell death versus growth inhibition for an observed drug response.

Graphical Abstract