Cutaneous melanoma is endowed with a high metastatic potential, possibly due to the elevated migratory capability of the cells originating the tumor, the melanocytes . The primary metastatic site is the draining lymph nodes and, as in most solid cancers, nodal status is a relevant predictor of patients’ outcome. When the malignancy goes beyond the regional lymph nodes and invades distant tissues, the overall survival of the patients is very short. Indeed, patients succumb to metastatic burden .
Even if significant progress has been made in the treatment of metastatic melanoma, few therapies are currently available. Lately, two agents, ipilimumab, a human IgG1 monoclonal antibody activating CTL-4 lymphocytes to melanoma cell killing, and vemurafenib, a potent inhibitor of mutant BRAF, have shown promising results in late-stage melanoma. Ipilimumab shows an improvement of 2.1 months of the overall survival when used in combination with dacarbazine, and a long-term and durable response , while vemurafenib, thus improving the rate of overall and progression-free survival of the patients, shows responses that are rarely durable . Moreover, the therapy based on BRAF inhibitors can only be used in approximately 60% of the melanomas, those harboring a BRAF V600 mutation . Very recently, combination therapies involving the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have been approved by the US FDA. These inhibitors are the first drugs approved for the combination treatment of melanoma, based on a solid understanding of the biological pathways of the disease . This approval clearly demonstrates the importance of continuing to investigate and dissect the cellular pathways, as well as the mechanisms of metastatic progression in melanoma, to design more appropriate and effective drugs to be used as single or combination therapies.