KIT Suppresses BRAF V600E -Mutant Melanoma by Attenuating Oncogenic RAS/MAPK Signaling

The receptor tyrosine kinase KIT promotes survival and migration of melanocytes during development, and excessive KIT activity hyperactivates the RAS/MAPK pathway and can drive formation of melanomas, most notably of rare melanomas that occur on volar and mucosal surfaces of the skin. The much larger fraction of melanomas that occur on sun-exposed skin is driven primarily by BRAF- or NRAS-activating mutations, but these melanomas exhibit a surprising loss of KIT expression, which raises the question of whether loss of KIT in these tumors facilitates tumorigenesis. To address this question, we introduced a mutation into a strain of melanoma-prone zebrafish. Melanoma onset was accelerated in fish. Tumors from animals were more invasive and had higher RAS/MAPK pathway activation. KIT knockdown also increased RAS/MAPK pathway activation in a BRAF -mutant human melanoma cell line. We found that pathway stimulation upstream of BRAF could paradoxically reduce signaling downstream of BRAF , and wild-type BRAF was necessary for this effect, suggesting that its activation can dampen oncogenic BRAF signaling. , expression of wild-type BRAF delayed melanoma onset, but only in a -dependent manner. Together, these results suggest that KIT can activate signaling through wild-type RAF proteins, thus interfering with oncogenic BRAF -driven melanoma formation. .