BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
KIT mutations and amplifications are the most common genetic alterations in melanomas arising in acral, mucosal, and chronically sun-damaged skin. Although KIT mutations are found in only 1% of all melanomas, they are reported in 10% of acral and 10% of mucosal melanomas . Less than 10% of KIT mutant melanomas contain BRAF or NRAS mutations.
c-KIT encodes the receptor tyrosine kinase for stem cell factor. In response to ligand binding, KIT activates signaling of pathways such as RAS. The most commonly observed KIT variant in melanoma, found in a third of KIT-mutant melanomas, is L576P . Activating mutations such as L576P promote melanocyte growth and survival by causing constitutive stimulation of MAPK and PI3K/AKT signaling. KIT mutations are associated with poorer clinical outcomes in acral and mucosal melanoma .
Fig. 2.2. The MITF axis. In melanocytes, microphthalmia-associated transcription factor (MITF) is expressed in response to melanocortin 1 receptor (MC1R) signaling upon binding of melanocyte-stimulating hormone (MSH). Non-signaling variants of MC1R are associated with the red hair/fair skin phenotype and increased melanoma susceptibility. MITF activity is modulated by phosphorylation, sumoylation, and ubiquitination. MITF target genes include regulators of differentiation and pigmentation as well as proliferation and survival. c-KIT signaling is essential for melanocyte development. c-KIT, NRAS, BRAF, and MITF are known melanoma oncogenes in the c-KIT pathway. SCF stem cell factor, cAMP cyclic AMP, PKA protein kinase A; CREB cAMP-responsive element-binding protein
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