Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression.
Although many melanomas harbor either activating mutations in BRAF or NRAS, there remains a substantial, yet little known, group of tumors without either mutation. Here, we used a genomic strategy to define a novel group of melanoma cell lines with co-overexpression of cyclin-dependent kinase 4 (CDK4) and KIT. Although this subgroup lacked any known KIT mutations, they had high phospho-KIT receptor expression, indicating receptor activity. Quantitative PCR confirmed the existence of a similar KIT/CDK4 subgroup in human melanoma samples. Pharmacologic studies showed the KIT/CDK4-overexpressing subgroup to be resistant to BRAF inhibitors but sensitive to imatinib in both in vitro and in vivo melanoma models. Mechanistically, imatinib treatment led to increased apoptosis and G(1) phase cell cycle arrest associated with the inhibition of phospho-ERK and increased expression of p27(KIP). Other melanoma cell lines, which retained some KIT expression but lacked phospho-KIT, were not sensitive to imatinib, suggesting that KIT expression alone is not predictive of response. We suggest that co-overexpression of KIT/CDK4 is a potential mechanism of oncogenic transformation in some BRAF/NRAS wild-type melanomas. This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy.
Smalley
Keiran S M
KS
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. K.smalley@mac.com
Contractor
Rooha
R
Nguyen
Thiennga K
TK
Xiao
Min
M
Edwards
Robin
R
Muthusamy
Viswanathan
V
King
Alastair J
AJ
Flaherty
Keith T
KT
Bosenberg
Marcus
M
Herlyn
Meenhard
M
Nathanson
Katherine L
KL
D000818:Animals; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018631:ras Proteins