Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas

Abstract

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. [Mol Cancer Ther 2008;7(9):2876 -83]

The CDK4/6 Inhibitor LY2835219 Overcomes Vemurafenib Resistance Resulting from MAPK Reactivation and Cyclin D1 Upregulation

“…Cyclin D1 was also demonstrated to be implicated in resistance to inhibitors of ERBB2, EGFR, and ER signaling (32,33). Recent studies suggest that cyclin D1 overexpression may be sufficient to render B-RAF V600E melanoma cells resistant to B-RAF inhibition (28). CCND1 is amplified in 11% of melanoma (2), including 17% of B-RAF V600E melanoma (28), indicating that it could be a mechanism of de novo resistance to B-RAF inhibitors.…”

“…Recent studies suggest that cyclin D1 overexpression may be sufficient to render B-RAF V600E melanoma cells resistant to B-RAF inhibition (28). CCND1 is amplified in 11% of melanoma (2), including 17% of B-RAF V600E melanoma (28), indicating that it could be a mechanism of de novo resistance to B-RAF inhibitors. Molecular analysis of our vemurafenib-resistant tumors revealed significant upregulation of cyclin D1 levels relative to parental tumors (Fig.…”

“…Inhibition of MAPK signaling by B-RAF inhibitors decreases cyclin D1 expression and upregulates CDK inhibitor p27 KIP1 levels, thus blocking cell-cycle entry in B-RAF V600E melanoma (26,27). Overexpression of cyclin D1 is linked to resistance to B-RAF inhibition (28). CCND1 is amplified in 11% of melanoma, including 17% of B-RAF V600E melanoma, thus suggesting a potential role of cyclin D1 in intrinsic resistance to B-RAF inhibitors (2,28).…”

“…Overexpression of cyclin D1 is linked to resistance to B-RAF inhibition (28). CCND1 is amplified in 11% of melanoma, including 17% of B-RAF V600E melanoma, thus suggesting a potential role of cyclin D1 in intrinsic resistance to B-RAF inhibitors (2,28). However, the role of cyclin D1 in acquired resistance to vemurafenib has not been described, and the therapeutic value of targeting cyclin D1/Rb axis to overcome vemurafenib resistance has not been explored.…”

BRAF, a target in melanoma

“…The genetic alterations in p16, cyclin D, and CDK4 that are identified commonly in melanoma point to that signaling complex as a potential target for combination therapy, and preclinical evidence supports this strategy in BRAF mutant melanoma. 85 Currently, the only drug strategy that exists to target these cell cycle regulators is CDK4 inhibition. Inhibitors of cyclin-dependent kinases, with some selectivity for CDK4, are in clinical development.…”