The phosphatidyl inositol 3‐kinase pathway is central to the pathogenesis of Kit‐activated melanoma

Mouse Kit L575P, the ortholog of human KIT L576P, a common KIT mutation found in human melanoma was expressed in an immortalized but non‐transformed mouse Ink4a‐Arf‐deficient melanocyte cell line. The resultant Ink4a‐Arf‐deficient Kit L575P‐expressing melanocytes exhibited increased proliferation, the ability to grow in soft agar, and increased migration. When these cells were injected subcutaneously into NOD/SCID/gamma(c) mice, melanomas arose in 5 of 7 (71%) mice. One of seven mice (14%) injected with these cells developed metastatic disease. Evaluation of signal transduction pathways downstream of constitutively activated Kit L575P revealed striking activation of the phosphatidyl inositol 3‐kinase (PI3K) pathway. Inhibition of the PI3K pathway pharmacologically or genetically abolished the transformation phenotypes gained by the L575P single mutant. These studies validate this Kit L575P‐activated model of melanoma and establish the PI3K pathway as a dominant signaling pathway downstream of Kit in melanoma.