PT - JOURNAL ARTICLE AU - Robert Vogel AU - Amir Erez AU - Grégoire Altan-Bonnet TI - Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis AID - 10.1101/038000 DP - 2016 Jan 01 TA - bioRxiv PG - 038000 4099 - http://biorxiv.org/content/early/2016/01/29/038000.short 4100 - http://biorxiv.org/content/early/2016/01/29/038000.full AB - Despite progress in developing small molecule inhibitors, a quantitative understanding of drug action in the physiological context of cells is lacking. Here, we apply single-cell analysis of signal transduction and proliferation to probe cellular responses to small molecule inhibitors. We use the model of cellular activation of T lymphocytes responding to cytokines and antigens. We uncover two distinct modes of drug action, in terms of signaling inhibition: digital inhibition (e.g. when the fraction of activated cells diminishes upon drug treatment, but cells remaining active appear unperturbed), and analog inhibition (e.g. when the fraction of activated cells is unperturbed while their overall activation is diminished). We introduce a computational model of the signaling cascade in order to account for such dichotomy. We test the predictions of our model in terms of the phenotypic variability of cellular responses under drug inhibition. Finally, we demonstrate that the digital/analog dichotomy of cellular response as revealed on short timescales with signal transduction, translates into similar dichotomy on long timescales. Overall, our analysis of drug action at the single cell level illustrates the strength of quantitative approaches to translate the promise of in vitro pharmacology into functionally-relevant cellular settings.