Dichotomy of cellular inhibition by small-molecule inhibitors revealed by single-cell analysis.

ABSTRACT: Despite progress in drug development, a quantitative and physiological understanding of how small-molecule inhibitors act on cells is lacking. Here, we measure the signalling and proliferative response of individual primary T-lymphocytes to a combination of antigen, cytokine and drug. We uncover two distinct modes of signalling inhibition: digital inhibition (the activated fraction of cells diminishes upon drug treatment, but active cells appear unperturbed), versus analogue inhibition (the activated fraction is unperturbed whereas activation response is diminished). We introduce a computational model of the signalling cascade that accounts for such inhibition dichotomy, and test the model predictions for the phenotypic variability of cellular responses. Finally, we demonstrate that the di

SUBMITTER: Vogel RM 

PROVIDER: S-EPMC5056434 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature