Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines
Malignant melanomas (MMs) are the abnormal proliferation of melanocytes and are one of the lethal skin cancers in humans, equines, and canines. Accordingly, MMs in companion animals can serve as naturally occurring animal models, completing conventional cancer models. The common constitutive activat...
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MDPI AG
2024-02-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/15/2/202 |
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| author | Yu Gao Eva-Maria Packeiser Sophia Wendt Anett Sekora Jessika-Maximiliane V. Cavalleri Barbara Pratscher Moosheer Alammar Maja Hühns Bertram Brenig Christian Junghanss Ingo Nolte Hugo Murua Escobar |
| author_facet | Yu Gao Eva-Maria Packeiser Sophia Wendt Anett Sekora Jessika-Maximiliane V. Cavalleri Barbara Pratscher Moosheer Alammar Maja Hühns Bertram Brenig Christian Junghanss Ingo Nolte Hugo Murua Escobar |
| author_sort | Yu Gao |
| collection | DOAJ |
| description | Malignant melanomas (MMs) are the abnormal proliferation of melanocytes and are one of the lethal skin cancers in humans, equines, and canines. Accordingly, MMs in companion animals can serve as naturally occurring animal models, completing conventional cancer models. The common constitutive activation of the MAPK and PI3K pathways in MMs has been described in all three species. Targeting the related pathways is considered a potential option in comparative oncologic approaches. Herein, we present a cross-species comparative analysis exposing a set of ten melanoma cell lines (one human, three equine, and six canine) derived from primary tumors or metastasis to a pan-RAF and RAF dimer inhibitor (LY3009120). Cellular response (proliferation, biomass, metabolism, early and late apoptosis/necrosis, and morphology) and the presence of pathogenic single-nucleotide variants (SNVs) within the mutational hotspot genes <i>BRAF</i> exon 11 and 15, <i>NRAS</i> exon 2 and 3, <i>KRAS</i> exon 2, and <i>KIT</i> exon 11 were analyzed. This study showed that equine malignant melanoma (EMM) cells (MelDuWi) harbor the <i>KRAS</i> p.Q61H mutation, while canine malignant melanoma (CMM) cells (cRGO1 and cRGO1.2) carry <i>NRAS</i> p.G13R. Except for EMM metastasis cells eRGO6 (wild type of the above-mentioned hotspot genes), all melanoma cell lines exhibited a decrease in dose dependence after 48 and 72 h of exposure to LY3009120, independent of the mutation hotspot landscape. Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in all melanoma cell lines except for eRGO6. The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the <i>NRAS</i> p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology. |
| first_indexed | 2024-03-07T22:31:26Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-07T22:31:26Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-391a145a1b6f4fc4a5db885dcf67b0d82024-02-23T15:17:49ZengMDPI AGGenes2073-44252024-02-0115220210.3390/genes15020202Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell LinesYu Gao0Eva-Maria Packeiser1Sophia Wendt2Anett Sekora3Jessika-Maximiliane V. Cavalleri4Barbara Pratscher5Moosheer Alammar6Maja Hühns7Bertram Brenig8Christian Junghanss9Ingo Nolte10Hugo Murua Escobar11Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, GermanyDepartment of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, GermanyDepartment of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, GermanyDepartment of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, GermanyClinical Unit of Equine Internal Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaClinical Unit of Equine Internal Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, AustriaDepartment of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, GermanyInstitute of Pathology, University Medicine of Rostock, Strempelstrasse, 18055 Rostock, GermanyInstitute of Veterinary Medicine, Division of Molecular Biology of Livestock and Molecular Diagnostics, Georg-August-University of Göttingen, 37077 Göttingen, GermanyDepartment of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, GermanyDepartment of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, GermanyDepartment of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, GermanyMalignant melanomas (MMs) are the abnormal proliferation of melanocytes and are one of the lethal skin cancers in humans, equines, and canines. Accordingly, MMs in companion animals can serve as naturally occurring animal models, completing conventional cancer models. The common constitutive activation of the MAPK and PI3K pathways in MMs has been described in all three species. Targeting the related pathways is considered a potential option in comparative oncologic approaches. Herein, we present a cross-species comparative analysis exposing a set of ten melanoma cell lines (one human, three equine, and six canine) derived from primary tumors or metastasis to a pan-RAF and RAF dimer inhibitor (LY3009120). Cellular response (proliferation, biomass, metabolism, early and late apoptosis/necrosis, and morphology) and the presence of pathogenic single-nucleotide variants (SNVs) within the mutational hotspot genes <i>BRAF</i> exon 11 and 15, <i>NRAS</i> exon 2 and 3, <i>KRAS</i> exon 2, and <i>KIT</i> exon 11 were analyzed. This study showed that equine malignant melanoma (EMM) cells (MelDuWi) harbor the <i>KRAS</i> p.Q61H mutation, while canine malignant melanoma (CMM) cells (cRGO1 and cRGO1.2) carry <i>NRAS</i> p.G13R. Except for EMM metastasis cells eRGO6 (wild type of the above-mentioned hotspot genes), all melanoma cell lines exhibited a decrease in dose dependence after 48 and 72 h of exposure to LY3009120, independent of the mutation hotspot landscape. Furthermore, LY3009120 caused significant early apoptosis and late apoptosis/necrosis in all melanoma cell lines except for eRGO6. The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the <i>NRAS</i> p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.https://www.mdpi.com/2073-4425/15/2/202equine malignant melanomacanine malignant melanomaPan-RAF inhibitorLY3009120DNA sequencinggenetic evaluation |
| spellingShingle | Yu Gao Eva-Maria Packeiser Sophia Wendt Anett Sekora Jessika-Maximiliane V. Cavalleri Barbara Pratscher Moosheer Alammar Maja Hühns Bertram Brenig Christian Junghanss Ingo Nolte Hugo Murua Escobar Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines Genes equine malignant melanoma canine malignant melanoma Pan-RAF inhibitor LY3009120 DNA sequencing genetic evaluation |
| title | Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines |
| title_full | Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines |
| title_fullStr | Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines |
| title_full_unstemmed | Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines |
| title_short | Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines |
| title_sort | cross species comparison of the pan raf inhibitor ly3009120 s anti tumor effects in equine canine and human malignant melanoma cell lines |
| topic | equine malignant melanoma canine malignant melanoma Pan-RAF inhibitor LY3009120 DNA sequencing genetic evaluation |
| url | https://www.mdpi.com/2073-4425/15/2/202 |
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