Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation
Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sam...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/4/829 |
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| author | Luca Hegedüs Özlem Okumus Elisabeth Livingstone Marcell Baranyi Ildikó Kovács Balázs Döme József Tóvári Ágnes Bánkfalvi Dirk Schadendorf Clemens Aigner Balázs Hegedüs |
| author_facet | Luca Hegedüs Özlem Okumus Elisabeth Livingstone Marcell Baranyi Ildikó Kovács Balázs Döme József Tóvári Ágnes Bánkfalvi Dirk Schadendorf Clemens Aigner Balázs Hegedüs |
| author_sort | Luca Hegedüs |
| collection | DOAJ |
| description | Spitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib—but not selumentinib—and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib. |
| first_indexed | 2024-03-09T00:51:00Z |
| format | Article |
| id | doaj.art-e2daa8b23a2b40f8ab575f817ad0edd9 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:51:00Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-e2daa8b23a2b40f8ab575f817ad0edd92023-12-11T17:15:30ZengMDPI AGCancers2072-66942021-02-0113482910.3390/cancers13040829Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent MutationLuca Hegedüs0Özlem Okumus1Elisabeth Livingstone2Marcell Baranyi3Ildikó Kovács4Balázs Döme5József Tóvári6Ágnes Bánkfalvi7Dirk Schadendorf8Clemens Aigner9Balázs Hegedüs10Department of Thoracic Surgery, University Medicine Essen–Ruhrlandklinik, Tüschener Weg 40, 45239 Essen, GermanyDepartment of Thoracic Surgery, University Medicine Essen–Ruhrlandklinik, Tüschener Weg 40, 45239 Essen, GermanyDepartment of Dermatology, University Medicine Essen, Esmarchstraße 14, 45147 Essen, Germany2nd Department of Pathology, Semmelweis University, Üllői út 93, 1091 Budapest, HungaryNational Korányi Institute of Pulmonology, Pihenő út 1, 1122 Budapest, HungaryNational Korányi Institute of Pulmonology, Pihenő út 1, 1122 Budapest, HungaryDepartment of Experimental Pharmacology, National Institute of Oncology, Ráth György u. 7-9, 1122 Budapest, HungaryDepartment of Pathology, University Medicine Essen, Hufelandstraße 55, 45147 Essen, GermanyDepartment of Dermatology, University Medicine Essen, Esmarchstraße 14, 45147 Essen, GermanyDepartment of Thoracic Surgery, University Medicine Essen–Ruhrlandklinik, Tüschener Weg 40, 45239 Essen, GermanyDepartment of Thoracic Surgery, University Medicine Essen–Ruhrlandklinik, Tüschener Weg 40, 45239 Essen, GermanySpitzoid melanoma is a rare malignancy with histological characteristics similar to Spitz nevus. It has a diverse genetic background and in adults, a similarly grim clinical outcome as conventional malignant melanoma. We established a spitzoid melanoma cell line (PF130) from the pleural effusion sample of a 37-year-old male patient. We found that the cell line carries a rare MEK1 mutation (pGlu102_Lys104delinsGln) that belongs to the RAF- and phosphorylation-independent subgroup of MEK1 alternations supposedly insensitive to allosteric MEK inhibitors. The in vivo tumorigenicity was tested in three different models by injecting the cells subcutaneously, intravenously or into the thoracic cavity of SCID mice. In the intrapleural model, macroscopic tumors formed in the chest cavity after two months, while subcutaneously and intravenously delivered cells showed limited growth. In vitro, trametinib—but not selumentinib—and the ATP-competitive MEK inhibitor MAP855 strongly decreased the viability of the cells and induced cell death. In vivo, trametinib but not MAP855 significantly reduced tumor growth in the intrapleural model. To the best of our knowledge, this is the first patient-derived melanoma model with RAF- and phosphorylation-independent MEK mutation and we demonstrated its sensitivity to trametinib.https://www.mdpi.com/2072-6694/13/4/829metastatic melanomaspitzoid melanomatargeted therapyMEK mutationMEK inhibitor |
| spellingShingle | Luca Hegedüs Özlem Okumus Elisabeth Livingstone Marcell Baranyi Ildikó Kovács Balázs Döme József Tóvári Ágnes Bánkfalvi Dirk Schadendorf Clemens Aigner Balázs Hegedüs Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation Cancers metastatic melanoma spitzoid melanoma targeted therapy MEK mutation MEK inhibitor |
| title | Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation |
| title_full | Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation |
| title_fullStr | Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation |
| title_full_unstemmed | Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation |
| title_short | Allosteric and ATP-Competitive MEK-Inhibition in a Novel Spitzoid Melanoma Model with a RAF- and Phosphorylation-Independent Mutation |
| title_sort | allosteric and atp competitive mek inhibition in a novel spitzoid melanoma model with a raf and phosphorylation independent mutation |
| topic | metastatic melanoma spitzoid melanoma targeted therapy MEK mutation MEK inhibitor |
| url | https://www.mdpi.com/2072-6694/13/4/829 |
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