Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas.
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.
Smalley
Keiran S M
KS
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. k.smalley@mac.com
Lioni
Mercedes
M
Dalla Palma
Maurizia
M
Xiao
Min
M
Desai
Brijal
B
Egyhazi
Suzanne
S
Hansson
Johan
J
Wu
Hong
H
King
Alastair J
AJ
Van Belle
Patricia
P
Elder
David E
DE
Flaherty
Keith T
KT
Herlyn
Meenhard
M
Nathanson
Katherine L
KL
D019943:Amino Acid Substitution / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005784:Gene Amplification / Q000187:drug effects; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014633:Valine / Q000235:genetics
D007093:Imidazoles; C508204:SB-590885; D019938:Cyclin D1; D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051358:Cyclin-Dependent Kinase 4; D014633:Valine
Clin Cancer Res. 2008 Jan 1;14(1):230-9
18172275
J Clin Oncol. 2006 Sep 10;24(26):4340-6
16908931
Cancer Res. 2002 Jun 1;62(11):3200-6
12036934
J Med Genet. 2004 Apr;41(4):270-2
15060100
J Clin Pathol. 2005 Nov;58(11):1163-9
16254105
Br J Cancer. 2007 Feb 12;96(3):445-9
17245336
J Clin Oncol. 2004 Nov 15;22(22):4456-62
15483017
Nature. 2007 Feb 22;445(7130):851-7
17314971
Nature. 2006 Jan 19;439(7074):358-62
16273091
Int J Cancer. 2003 May 1;104(5):527-32
12594806
Oncogene. 2003 May 19;22(20):3053-62
12789280
Bioinformatics. 2004 Dec 12;20(18):3656-8
15247094
Nucleic Acids Res. 2003 Jan 1;31(1):51-4
12519945
Cancer Res. 2006 Mar 15;66(6):2946-52
16540642
Oncogene. 2005 May 12;24(21):3459-71
15735667
Breast Cancer Res. 2005;7(6):R1186-98
16457699
Bioinformatics. 2005 Mar;21(6):821-2
15531610
Am J Pathol. 2005 May;166(5):1541-54
15855653
Genes Chromosomes Cancer. 1999 Aug;25(4):339-48
10398427
Cancer Res. 2007 Apr 15;67(8):3594-600
17440070
J Clin Oncol. 2005 Aug 10;23(23):5281-93
16009947
Genes Chromosomes Cancer. 2006 May;45(5):447-54
16419059
Cancer Res. 2006 Dec 1;66(23):11100-5
17145850
N Engl J Med. 2005 Nov 17;353(20):2135-47
16291983
Genome Res. 2004 Jan;14(1):179-87
14672980
J Invest Dermatol. 2005 Dec;125(6):1242-51
16354195
Mol Cancer Ther. 2006 May;5(5):1136-44
16731745