Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas

• Published in: International journal of cancer 2009-02, Vol.124 (4), p.862-868
• Main Authors: Ashida, Atsuko, Takata, Minoru, Murata, Hiroshi, Kido, Kenji, Saida, Toshiaki
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - pharmacology; Biological and medical sciences; Dermatology; Female; Humans; Indoles - pharmacology; Male; Medical sciences; melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Middle Aged; molecular targets; mucous membrane; Mucous Membrane - pathology; Mutation; Neoplasm Metastasis; oncogene mutation; Phosphorylation; Proto-Oncogene Proteins c-kit - metabolism; Pyrroles - pharmacology; skin; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Stem Cell Factor - metabolism; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24048

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. © 2008 Wiley‐Liss, Inc.