LAUSR

Simple Summary Inside a tumor mass, drug resistant and sensitive cell populations co-exist, leading to a therapeutic challenge in oncology. In this study, we developed 2D and 3D co-culture systems and mathematical modeling to better understand how these different populations impact each other. We demonstrated that drug-sensitive cell populations inhibit the growth of drug-resistant populations. Mathematical modeling predicted that metronomic schedules, using chronic administration of drugs at low doses, could better control intratumor cell dynamics. We validated our in silico data in 3D and in vivo models. Finally, we demonstrated that metabolic cell activity of drug-sensitive cells could play a key role in controlling the proliferation of drug-resistant cells. Altogether, our study reports a new mechanism of action of metronomic therapy and paves the way for using it to better control drug resistance. Abstract Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is a widely observed phenomenon in advanced cancers, mainly due to intratumor clonal heterogeneity. How tumor clones progress and impact each other remains elusive. In this study, we developed 2D and 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematical model to better understand clone dynamics. Our results demonstrated that the drug-sensitive clones inhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictions and their experimental in vitro and in vivo validations indicated that a metronomic schedule leads to a better regulation of tumor cell heterogeneity over time than a maximum-tolerated dose schedule, while achieving control of tumor progression. We finally showed that drug-sensitive and -resistant clones exhibited different metabolic statuses that could be involved in controlling the intratumor heterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones could play a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computational and experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism to manage intratumor heterogeneity.