Melanoma is the most aggressive of the cutaneous
malignancies, causing more than 9,000 deaths in the past year in the United States. Historically, systemic
therapies have been largely ineffective, because
melanoma is usually resistant to cytotoxic
chemotherapy. However, during the past few years, several targeted
therapies have proved effective in this challenging disease. These recent advances have been facilitated by an improved understanding of the driving genetic aberrations of
melanoma, particularly mutations in the
mitogen-activated protein kinase (MAPK) pathway.
Vemurafenib, a BRAF inhibitor, demonstrated an overall survival advantage in phase III trials and is an appropriate option for first-line
therapy in metastatic BRAF mutant
melanoma.
Dabrafenib, another BRAF inhibitor, and
trametinib, a
MEK inhibitor, also have been shown to be effective in phase III trials for BRAF mutant
melanoma and may be additional treatment options as monotherapy or in combination pending regulatory approval. Additionally,
imatinib is a promising targeted
therapy for patients whose
tumors harbor a KIT mutation in exons 11 and 13. Although these targeted agents cause objective responses and clinical benefit in patients with metastatic
melanoma, resistance invariably develops. New targets and strategies to overcome acquired resistance are urgently needed. Furthermore, no effective targeted
therapy has been developed for NRAS mutant
tumors or in
melanomas with as yet unknown driver mutations. In this review, we discuss current molecular targeted treatment options and promising ongoing research to develop new strategies to treat
melanoma.