Functional heterogeneity within the population of tumor cells underlies the wide variety of cellular responses against therapies. Patient-derived tumor organoids recapitulate the histopathological features of native tumors, including patient specific responses towards therapies. Using established biobanks of patient-derived tumor organoid, we perform drug screens to understand genotype-phenotype correlations, in particular concerning RAS pathway mutations. In addition to classical high-throughput drug screens, we develop new strategies for imaging-based drug sensitivity measurements. Most recently, we developed real-time single-cell drug response measurements in patient-derived tumor organoids using FRET-based quantitative read-out of ERK activity, the downstream effector protein of the RAS pathway. We are intrigued by single-cell drug responses towards targeted inhibitors of the RAS pathway in the context of population dynamics and therapy resistance.