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To date, the emergence of drug resistance is never dealt with until it occurs. Yet, studies have shown that treatment-sensitive and -resistant malignant cell subpopulations coexist within the same tumor. Being able to decipher their complex relationship and characterize the impact of intratumor heterogeneity on treatment efficacy is essential to understand tumor biology and define adaptive therapeutic strategies to overcome resistance. We developed 2D and 3D spheroid co-culture models to analyze the expansion of A549 (DsRed expressing) and A549-EpoB40 (GFP expressing) cells over time (for up to one month), which are drug-sensitive and -resistant lung carcinoma cells, respectively. The fluorescent signals were recorded daily to quantify and localize each tumor subpopulation. We showed that the sensitive cells constitute the predominant subpopulation in the absence of any chemotherapeutic treatment, since they have an unexpected suppressive effect on the growth of resistant cells (-79% at day 14, p Citation Format: Manon Carre, Maryna Bondarenko, Marie-Pierre Montero, Guillemette Chapuisat, Assia Benabdallah, Marion Le Grand, Diane Braguer, Nicolas Andre, Eddy Pasquier. Metronomic scheduling: a promising strategy to manage intratumor heterogeneity and control treatment resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2572. doi:10.1158/1538-7445.AM2015-2572