Synergistic anti-tumor activity and inhibition of angiogenesis by cotargeting of oncogenic and death receptor pathways in human melanoma.

The development of mutant BRAF (v-raf murine sarcoma viral oncogene homolog B)- and mitogen/extracellular signal-regulated kinase (MEK)-specific inhibitors, such as Vemurafenib, Dabrafenib and Trametinib, as well as of monoclonal antibodies targeting immune checkpoints, has markedly improved the treatment of advanced melanoma, as shown by highly significant effects, achieved in several trials, on progression-free and/or overall survival. 1 , 2 , 3 , 4 , 5 However, a fraction of patients does not benefit from target-specific therapy or immunotherapy, and duration of clinical responses may be limited. 1 , 2 , 3 , 4 , 5 Mechanisms of resistance to specific inhibitors 6 and of tumor escape from immune recognition 7 contribute to prevent induction of melanoma cell death by the new therapies and explain the urgent need for the identification of more effective approaches.

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