Several molecular mechanisms are involved in melanoma genesis and progression. Molecular targets for effective therapeutic intervention have been identified within the RAS-RAF-MEK-ERK and, to a less extent, PI3K-AKT pathways. The development of inhibitors of key effectors (mainly BRAF mutant, MEK, and KIT) into such pathways has significantly improved the treatment of patients with advanced melanoma. However, emerging data indicate that a large variety of acquired and intrinsic mechanisms may drive resistance to the main targeted inhibitors. All the evidence suggests that in melanoma, as probably in all types of cancer, it is unlikely that targeting a single component in pathogenetic signalling pathways could yield significant antitumour responses. Therefore, knowledge of the multiple altered signalling events involved in response and resistance to targeted treatments will allow for the development of more effective combination therapies, which may represent the next challenge for the management of patients with such a disease.
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