Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas.
Recent studies showed KIT gene aberrations in a substantial number of melanomas on acral skin and mucosa, suggesting the therapeutic benefit of tyrosine kinase inhibitors, such as imatinib. We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and mucosal melanomas. Immunohistochemistry revealed moderate or strong KIT protein expression in 13 (48%) tumors. Sequence analysis revealed K642E and D820Y mutations in two metastases. Amplification of KIT was identified by real-time PCR in 4 tumors, including one that had K642E. Western blot analysis showed phosphorylation of the KIT receptor in 8 (62%) of 13 cryopreserved samples, indicating the frequent pathological activation of the receptor in vivo. Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations, as well as in one tumor with KIT gene amplification. Furthermore, 5 tumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor. Expression of stem cell factor (SCF) in melanoma cells as well as stromal cells suggests SCF/KIT autocrine and paracrine activation in these tumors. Finally, we found significant growth suppressive effects of sunitinib in two acral melanoma cell lines; one harboring the D820Y mutation and one showing SCF-dependent KIT activation. These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and mucosal melanomas, and suggest a potential therapeutic benefit of sunitinib for these melanomas.
Ashida
Atsuko
A
Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Takata
Minoru
M
Murata
Hiroshi
H
Kido
Kenji
K
Saida
Toshiaki
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009092:Mucous Membrane / Q000473:pathology; D009154:Mutation; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019089:Stem Cell Factor / Q000378:metabolism; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib