Metabolism-oriented compound screen in physiological culture conditions identifies a NAMPT inhibitor highly effective against drug-naive and -resistant melanoma cells

Abstract

Many melanoma patients do not respond to therapy or rapidly develop resistance to MAPK pathway inhibitors and immune checkpoint blockade treatments, highlighting the urgent need for additional therapeutic strategies for these patients. To identify compounds that target drug-naive and -resistant melanoma cells (Encorafenib/Binimetinib-resistant), we performed a screen using a metabolism-oriented compound library in different cell culture media and growth conditions (2D and 3D). The efficacy of several compounds varied considerably under changing test conditions, but importantly, we also detected compounds that work across all tested conditions. In general, drug activity was reduced under hypoxia and in 3D spheroids. Thorough validation was performed for drugs showing potency in all conditions with a focus on efficacy in 3D spheroids grown in an in- house physiological culture medium. Using hydrogel matrix-embedded multi-cell type 3D models, we found that FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor, is very potently suppressing melanoma cell growth while not affecting the growth of healthy cells such as fibroblasts and endothelial cells.