Melanoma is one of the fastest growing tumor types in the United States. Immunotherapy and chemotherapy benefit only a few patients with metastatic disease. Therapy targeting a signaling pathway critical to the cancer's growth can provide dramatic benefit in several other malignancies and may be a valuable strategy for advanced melanoma, if drugs with a favorable therapeutic index are effective against essential molecular pathways. One such target is the V600E "gain-of-function" BRAF mutation found in 60% of melanomas; other mutations or molecular alterations cooperate with V600E BRAF, particularly those that cause loss of function of PTEN, upstream of Akt and mammalian target of rapamycin. Rapid development of new agents, a better understanding of the target pathways and mechanisms of resistance, and carefully designed strategies to optimize combinations and sequences of these agents, potentially with chemotherapy or immunotherapy, may ultimately have the potential to overcome the previously insurmountable obstacle of therapy resistance in melanoma.
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