Drug dose-response measurements are the cornerstone of pre-clinical assessments of new and existing therapeutics. As a means to identify biomarkers of drug response, high-throughput studies have attempted to relate drug sensitivity across hundreds of cell lines and hundreds of drugs to inhibition of mitogensis and induction of apoptosis. And, by analogy with antibiotic susceptibility testing, it is increasingly possible to screen primary human tumor cells as a means to personalize therapy for individual patients.
GR metrics to accurately parameterize drug responses.
The metrics usually used to parameterize drug response (IC50, Emax, or AUC) are based on assessing the cell count of a treated condition relative to an untreated control. All of these metrics suffer from a fundamental flaw: cell lines divide at very different rates and those that undergo more divisions over the course of an assay are scored as more sensitive than cell lines with fewer divisions, even if their inherent drug sensitivities are identical. We developed a new method to parameterize drug response, the growth rate inhibition (GR) metrics, which is based on the ratio of growth rates under treatment conditions in relation to an untreated control. GR metrics are independent of cell growth over the course of the experiment and thus enable us to accurately compare cell lines with varying growth rates or experimental conditions that can alter growth rates.
Reanalyzing high-throughput pharmacogenomic datasets.
A recently published large-scale pharmacogenomic study released the division times of all cell lines together with the classical IC metris. This allowed us to reanalyze the data and show that quantification of drug sensitivity based on the normalized growth rate inhibition (GR) values are not plagued by false positive or false negative pharmacogenomics associations driven by division rate. In addition, unlike Emax, drug efficacy as measured by GRmax is directly related to the phenotype of the response and carries information complementary to drug potency defined by GR50.
Methods for accurate and reproducible measurement of drug responses.
In the past two years we developed numerous advances in how to accurately and reproducibly measure drug responses. To make these advances freely available to all researchers, we are working on a protocol paper describing the experimental and computational approach to measure drug response. We are also releasing a methods paper that describes a new way to easily and accurately count live cells using plate microscopy. Finally, as part of a LINCS project, we are showing how applying all these techniques allows four independent labs to measure drug responses with little variability-- a pre-requisite for joint or follow-up studies between different labs.