English
Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines.
Abstract: 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 exon 11 and 15, exon 2 and 3, exon 2, and exon 11 were analyzed. This study showed that equine malignant melanoma (EMM) cells (MelDuWi) harbor the p.Q61H mutation, while canine malignant melanoma (CMM) cells (cRGO1 and cRGO1.2) carry 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 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.
Publication Date: 2024-02-03
PubMed ID: 38397192PubMed Central: PMC10887541DOI: 10.3390/genes15020202Google Scholar: Lookup
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Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
This research article examines the anti-tumor effects of a drug called LY3009120 on malignant melanomas, a type of deadly skin cancer, in humans, horses, and dogs. The study involved exposure to the drug in a variety of melanoma cell lines, and analysed both cell response and presence of specific genetic mutations. While most cell lines showed responses to the drug, including decreased proliferation and increased apoptosis, some displayed resistance, making them useful for future study on resistance in oncology.
Research Context and Methods
- The research aims to understand the anti-tumor effects of the pan-RAF and RAF dimer inhibitor LY3009120 on malignant melanomas, a type of lethal skin cancer commonly found in humans, horses, and dogs.
- The cancer cells for the study were extracted from primary tumors or metastasis sites. The collection constituted of one human, three equine, and six canine melanoma cell lines.
- The study then involved exposing these melanoma cell lines to LY3009120 and analysing changes in various cellular responses, such as proliferation, biomass, metabolism, and morphology, along with early and late apoptosis or necrosis.
- The presence of specific single-nucleotide variants (SNVs) or genetic mutations within hotspot genes were also studied.
Research Findings
- The study identified the presence of p.Q61H mutations in equine malignant melanoma cells (MelDuWi) and p.G13R mutations in canine malignant melanoma cells (cRGO1 and cRGO1.2).
- Except for one set of cells from equine metastasis (eRGO6), which had a wild type of the hotspot genes, all melanoma cell lines showed a decrease in proliferation and an increase in early or late apoptosis/necrosis after 48 and 72 hours of exposure to LY3009120.
- The research, therefore, highlights that the effects of LY3009120 were largely consistent across species and were not primarily influenced by the presence or absence of hotspot gene mutations.
- Importantly, the study revealed that irradiation-resistant canine metastasis cells (cRGO1.2) harboring the p.G13R mutation were significantly sensitive to LY3009120, whereas the equine metastasis-derived eRGO6 cells were resistant to it, providing crucial information for future research focused on understanding resistance mechanisms in cancer therapy.
Implications of the Study
- The findings suggest that LY3009120 could have potential as a cancer treatment across species, with the drug effectively triggering apoptosis and reducing proliferation in nine out of ten melanoma cell lines, regardless of the presence of specific mutations.
- The study also creates avenues for future research in comparative oncology by identifying two cell lines with significant resistance or sensitivity to LY3009120, aiding in further investigations into resistance mechanisms in cancer treatment.
Cite This Article
APA
Gao Y, Packeiser EM, Wendt S, Sekora A, Cavalleri JV, Pratscher B, Alammar M, Hu00fchns M, Brenig B, Junghanss C, Nolte I, Murua Escobar H.
(2024).
Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120’s Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines.
Genes (Basel), 15(2), 202.
https://doi.org/10.3390/genes15020202
Publication
Researcher Affiliations
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
- Clinical Unit of Equine Internal Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
- Clinical Unit of Equine Internal Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
- Clinical Unit of Small Animal Internal Medicine, Department for Companion Animals and Horses, University of Veterinary Medicine Vienna, 1210 Vienna, Austria.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
- Institute of Pathology, University Medicine of Rostock, Strempelstrasse, 18055 Rostock, Germany.
- Institute of Veterinary Medicine, Division of Molecular Biology of Livestock and Molecular Diagnostics, Georg-August-University of Gu00f6ttingen, 37077 Gu00f6ttingen, Germany.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
- Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany.
- Department of Medicine, Clinic III, Hematology, Oncology and Palliative Medicine, University Medical Center Rostock, 18057 Rostock, Germany.
MeSH Terms
- Humans
- Animals
- Dogs
- Horses
- Melanoma / drug therapy
- Melanoma / genetics
- Antineoplastic Agents / pharmacology
- Phosphatidylinositol 3-Kinases / metabolism
- Proto-Oncogene Proteins p21(ras)
- Proto-Oncogene Proteins B-raf / genetics
- Proto-Oncogene Proteins B-raf / metabolism
- Protein Kinase Inhibitors / pharmacology
- Skin Neoplasms
- Cell Line, Tumor
- Necrosis
- Phenylurea Compounds
- Pyrimidines
Grant Funding
- No.202006170058 / The China Scholarship Council (CSC)
Conflict of Interest Statement
The authors declare no conflicts of interest.
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