Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma
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 BRAF<sub>V600E</sub> signaling pathway media...
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/1963 |
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| author | Anne Uebel Stefanie Kewitz-Hempel Edith Willscher Kathleen Gebhardt Cord Sunderkötter Dennis Gerloff |
| author_facet | Anne Uebel Stefanie Kewitz-Hempel Edith Willscher Kathleen Gebhardt Cord Sunderkötter Dennis Gerloff |
| author_sort | Anne Uebel |
| collection | DOAJ |
| description | 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 BRAF<sub>V600E</sub> 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. |
| first_indexed | 2024-03-11T09:43:21Z |
| format | Article |
| id | doaj.art-f3565102c3ff4a38b9a04e1c0e7241c2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:43:21Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f3565102c3ff4a38b9a04e1c0e7241c22023-11-16T16:50:23ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243196310.3390/ijms24031963Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in MelanomaAnne Uebel0Stefanie Kewitz-Hempel1Edith Willscher2Kathleen Gebhardt3Cord Sunderkötter4Dennis Gerloff5Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyDepartment of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, 06120 Halle (Saale), GermanyActivating 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 BRAF<sub>V600E</sub> 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.https://www.mdpi.com/1422-0067/24/3/1963melanomaBRAFresistanceEZH2vemurafenib |
| spellingShingle | Anne Uebel Stefanie Kewitz-Hempel Edith Willscher Kathleen Gebhardt Cord Sunderkötter Dennis Gerloff Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma International Journal of Molecular Sciences melanoma BRAF resistance EZH2 vemurafenib |
| title | Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma |
| title_full | Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma |
| title_fullStr | Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma |
| title_full_unstemmed | Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma |
| title_short | Resistance to BRAF Inhibitors: EZH2 and Its Downstream Targets as Potential Therapeutic Options in Melanoma |
| title_sort | resistance to braf inhibitors ezh2 and its downstream targets as potential therapeutic options in melanoma |
| topic | melanoma BRAF resistance EZH2 vemurafenib |
| url | https://www.mdpi.com/1422-0067/24/3/1963 |
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