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Metronomic Chemotherapy Modulates Clonal Interactions to Prevent Drug Resistance in Non-Small Cell Lung Cancer
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International audience. :Despite recent advances in deciphering cancer drug resistance mechanisms, relapse is awidely 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 2Dand 3D non-small cell lung cancer co-culture systems and defined a phenomenological mathematicalmodel to better understand clone dynamics. Our results demonstrated that the drug-sensitive clonesinhibit the proliferation of the drug-resistant ones under untreated conditions. Model predictionsand their experimentalin vitroandin vivovalidations indicated that a metronomic schedule leadsto 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 -resistantclones exhibited different metabolic statuses that could be involved in controlling the intratumorheterogeneity dynamics. Our data suggested that the glycolytic activity of drug-sensitive clones couldplay a major role in inhibiting the drug-resistant clone proliferation. Altogether, these computationaland experimental approaches provide foundations for using metronomic therapy to control drug-sensitive and -resistant clone balance and highlight the potential of targeting cell metabolism tomanage intratumor heterogeneity.
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