Speaker
Description
The emergence of drug-tolerant cells in clonal cancer populations is the main cause of reduced cytotoxic drug efficacy. But these tolerant cells can also be used as a specific target to design drug combinations. In this study (\cite{peyre}), we investigate the response of clonal cancer cells to pro-apoptotic and pro-necroptotic drugs. In both cases, fractional killing increases upon repeated administration. However, transcriptomic analysis reveals that pro-apoptotic-tolerant cells resemble pro-necroptotic-sensitive cells — suggesting that alternating treatments could mitigate this effect, which we validate experimentally. We then present a population model of drug response phenotypic switch, based on ODEs, to understand the re-sensitization of tolerant cells. The model is calibrated independently for each drug then coupled into a unified system simulating transitions between the tolerant, apoptosis-sensitive and necroptosis-sensitive states. We demonstrate that cells adapt to treatment by modulating drug retention time via regulation of drug degradation rates and reveal that the majority of pro-apoptotic-tolerant cells are in fact sensitive to necroptosis; pro-apoptotic treatment only accelerating the transition from the tolerant state toward necroptotic sensitivity.
Bibliography
@article{peyre,
title={Transition between cell states of sensitivity reveals molecular vulnerability of drug-tolerant cells},
author={Peyre, Ludovic and P{\'e}r{\'e}, Marielle and Meyer, Mickael and Bian, Benjamin and Moureau-Barbato, Marina and Djema, Walid and Mari, Bernard and Vassaux, Georges and Roux, J{\'e}r{\'e}mie},
journal={Molecular Systems Biology},
volume={21},
number={12},
pages={1702},
year={2025}
}
