Integrating Phenotypic Search and Phosphoproteomic Profiling of Active Kinases for Optimization of Drug Mixtures for RCC Treatment

Simple Summary: Renal cell carcinoma (RCC) cancer is among the ten most common malignancies, and frequently presents as metastatic disease (mRCC). For these patients, systemic treatment is in order, but mRCC is often highly heterogeneous, and resistant to conventional therapies, or acquires resistance over time. Application of a combination of targeted therapeutic agents can tackle these problems, however, experimental optimization is not feasible given the enormous number of possible drug- and dose-combinations. We used a phenotypic approach, the streamlined-feedback system control (s-FSC) technique, which does not use a priori information on the mechanism of action of drugs. Using a number of searches, this method selects for optimized drug combinations (ODC) given at low doses (ED5-25), that can act synergistically. This way, we selected effective ODC for different RCC cell lines. Analysis of kinase activity was performed to provide mechanistic insight into the ODC action, and to further improve the found drug combinations.