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Title: Resistance to BRAF inhibitors : EZH2 and its downstream targets as potential therapeutic options in melanoma
Author(s): Uebel, Anne
Kewitz-Hempel, Stefanie
Willscher, Edith
Gebhardt, Kathleen
Sunderkötter, CordLook up in the Integrated Authority File of the German National Library
Gerloff, Dennis
Issue Date: 2023
Type: Article
Language: English
Abstract: Activating BRAF mutations occurs in 50–60% of malignant melanomas. Although initially treatable, the development of resistance to BRAF-targeted therapies (BRAFi) is a major challenge and limits their efficacy. We have previously shown that the BRAFV600E signaling pathway mediates the expression of EZH2, an epigenetic regulator related to melanoma progression and worse overall survival. Therefore, we wondered whether inhibition of EZH2 would be a way to overcome resistance to vemurafenib. We found that the addition of an EZH2 inhibitor to vemurafenib improved the response of melanoma cells resistant to BRAFi with regard to decreased viability, cell-cycle arrest and increased apoptosis. By next-generation sequencing, we revealed that the combined inhibition of BRAF and EZH2 dramatically suppresses pathways of mitosis and cell cycle. This effect was linked to the downregulation of Polo-kinase 1 (PLK1), a key regulator of cell cycle and proliferation. Subsequently, when we inhibited PLK1, we found decreased cell viability of melanoma cells resistant to BRAFi. When we inhibited both BRAF and PLK1, we achieved an improved response of BRAFi-resistant melanoma cells, which was comparable to the combined inhibition of BRAF and EZH2. These results thus reveal that targeting EZH2 or its downstream targets, such as PLK1, in combination with BRAF inhibitors are potential novel therapeutic options in melanomas with BRAF mutations.
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Journal Title: International journal of molecular sciences
Publisher: Molecular Diversity Preservation International
Publisher Place: Basel
Volume: 24
Issue: 3
Original Publication: 10.3390/ijms24031963
Appears in Collections:Open Access Publikationen der MLU

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