As our CRISPR screening and delineation of the downstream mechanisms underlying BRAFi and MAPKi resistance was limited to the cell line models that already established acquired resistance (e.g. A375VR, SK-mel-28VR) or intrinsic resistance (Hs294T) to therapy, future studies should elucidate metabolic rewiring involving polyamine biosynthesis, EIF5A hypusination and increased mitochondrial biogenesis in the complex process of adaptation, plasticity and acquisition of resistance in BRAFi and MAPKi treated melanoma. Here, EIF5A is linked to melanoma.