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Identification of a Novel Subgroup of Melanomas with KIT/Cyclin-Dependent Kinase-4 Overexpression

¹ The Wistar Institute, ² Department of Pathology and Laboratory Medicine, ³ Abramson Cancer Center, Divisions of ⁴ Hematology-Oncology and ⁵ Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; ⁶ Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont; and ⁷ GlaxoSmithKline, Collegeville, Pennsylvania

Requests for reprints: Keiran S.M. Smalley, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-898-0002; Fax: 215-898-0890; E-mail: K.smalley{at}mac.com.

Key Words: imatinib • KIT • melanoma

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 G₁ 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. [Cancer Res 2008;68(14):5743–52]