Melanoma mutagenesis and aberrant cell signaling.
BACKGROUND
Malignant melanoma is the most fatal type of skin cancer. Traditional melanoma classification has been based on histological subtype or anatomical location. However, recent evidence suggests that melanoma comprises a group of diseases characterized by distinct molecular mutations. These mutations affect disease behavior but provide unique opportunities for targeted therapy.


METHODS
In this review, several signaling pathways in melanoma are described as well as how mutations of BRAF, NRAS, KIT, GNAQ, and GNA11 genes cause aberrant signaling and malignant transformation.


RESULTS
Multiple genes affecting both the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway are mutated in melanoma. Melanomas harboring the BRAF V600E mutation have demonstrated sensitivity to both RAF and MAPK/extracellular signal regulated kinase (ERK) inhibitors in vitro and in vivo. In addition, KIT-mutant melanomas, often arising from mucosal, acral, and chronically sun-damaged skin surfaces, have shown clinical response to several inhibitors of the type III transmembrane receptor tyrosine kinase KIT. Uveal melanoma, which often harbors GNAQ or GNA11 mutations, may also be sensitive to MAPK/ERK or protein kinase C/PI3K pathway inhibition.


CONCLUSIONS
Emerging knowledge of these molecular alterations has led to clinical advances in patients with melanoma. The study of known mutations and identification of new potential targets must continue in an effort to develop more effective therapies for this disease.
Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. carvajar@mskcc.org.
Danielle M
DM
Bello
Charlotte E
CE
Ariyan
Richard D
RD
Carvajal
D000818:Animals; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016296:Mutagenesis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology