CFLAR and melanoma: c-FLIP, the main caspase-8 inhibitor, is overexpressed in melanoma lesions38 and is a main mechanism of melanoma resistance to TRAIL, as indicated by studies where c-FLIP downregulation was sufficient to render TRAIL-R2+ melanoma cells responsive to this death ligand.39 We found that both the AZD6244–BEZ235–TRAIL and the AZD6244–TRAIL combinations induced strong downmodulation of c-FLIPL and/or c-FLIPs isoforms, associated with caspase-8 activation, compared with single treatments and to the AZD6244–BEZ235 treatment.