Melanoma pathophysiology and drug targets

In fair-skinned populations, both incidence and mortality rates of melanoma have been increasing over the past decades. Melanoma incidence has been found to vary according to the population's origin, with the highest rates in Australia, the USA and North Europe. A combination of an intermittent exposure to UV radiation with endogenous factors, such as a light phototype, higher number of nevi and family history for melanoma increases the risk of the disease. Although several genetic and molecular alterations have been identified, pathogenesis of melanoma is mostly due to a sequence of interactions between key effectors in three molecular pathways: CDKN2A (with a role in both susceptibility and tumorigenesis), MAPK and PI3K/AKT. Demonstration that a complex molecular scenario underlies development and progression of the disease confirms the existence of several distinct subtypes of melanoma and, therefore, distinct subsets of patients with putative differences in tumor behavior (which may determine a wide range of variations in prognosis and response to therapy).