期刊
MOLECULAR CANCER THERAPEUTICS
卷 7, 期 9, 页码 2876-2883出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-08-0431
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资金
- NIH [CA76674, CA25874, CA10815, CA93372, CA47159, CA80999, CA098101, CA1 17881, GM071695]
- Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health
- Career Development Award from the National Cancer Institute-Specialized Programs of Research Excellence [CA93372]
- NATIONAL CANCER INSTITUTE [R01CA076674, R01CA047159, R01CA080999, P30CA010815, P01CA098101, P50CA093372, P01CA025874] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM071695] Funding Source: NIH RePORTER
Recent studies have shown that there is a considerable heterogeneity in the response of melanoma cell lines to MEK and BRAF inhibitors. In the current study, we address whether dysregulation of cyclin-dependent kinase 4 (CDK4) and/or cyclin D1 contribute to the BRAF inhibitor resistance of melanoma cells. Mutational screening identified a panel of melanoma cell lines that harbored both a BRAF V600E mutation and a CDK4 mutation: K22Q (1205Lu), R24C (WM39, WM46, and SK-Mel-28), and R24L (WM902B). Pharmacologic studies showed that the presence of a CDK4 mutation did not alter the sensitivity of these cell lines to the BRAF inhibitor. The only cell line with significant BRAF inhibitor resistance was found to harbor both a CDK4 mutation and a CCND1 amplification. Array comparative genomic hybridization analysis showed that CCND1 was amplified in 17% of BRAF V600E-mutated human metastatic melanoma samples, indicating the clinical relevance of this finding. As the levels of CCND1 amplification in cell lines are lower than those seen in clinical specimens, we overexpressed cyclin D1 alone and in the presence of CDK4 in a drug-sensitive melanoma line. Cyclin D1 overexpression alone increased resistance and this was enhanced when cyclin D1 and CDK4 were concurrently overexpressed. In conclusion, increased levels of cyclin D1, resulting from genomic amplification, may contribute to the BRAF inhibitor resistance of BRAF V600E-mutated melanomas, particularly when found in the context of a CDK4 mutation/overexpression.
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