1. Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways.
- Author
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Mannsåker TA, Hoang T, Aasen SN, Bjørnstad OV, Parajuli H, Sundstrøm T, and Thorsen FA
- Subjects
- Apoptosis genetics, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms secondary, Cell Line, Tumor, Cell Movement genetics, Cell Survival drug effects, Cell Survival genetics, Gene Expression Regulation, Neoplastic, Humans, Melanoma genetics, Melanoma metabolism, Melanoma pathology, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt metabolism, Receptor Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases metabolism, Signal Transduction genetics, Anilides pharmacology, Apoptosis drug effects, Cell Movement drug effects, Pyridines pharmacology, Signal Transduction drug effects
- Abstract
Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.
- Published
- 2021
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