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Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
Trond Are Mannsåker1, Tuyen Hoang1, Synnøve Nymark Aasen1
1Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
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.
Insights
Cabozantinib shows promise in treating melanoma brain metastasis (MBM). This drug reduced MBM cell viability, migration, and induced apoptosis, suggesting a new therapeutic avenue.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Melanoma frequently metastasizes to the brain, with limited treatment options for melanoma brain metastasis (MBM).
- Existing targeted therapies and immunotherapies show suboptimal efficacy in MBM patients.
- New therapeutic strategies are urgently needed for MBM.
Purpose of the Study:
- To investigate the anti-tumor activity of cabozantinib in human MBM cell lines.
- To explore the molecular mechanisms underlying cabozantinib's effects on MBM cells.
Main Methods:
- Treatment of three human MBM cell lines with cabozantinib in monolayer and spheroid cultures.
- Assessment of cell viability, migration, and apoptosis.
- Analysis of phosphorylated receptor tyrosine kinases (RTKs) using a p-RTK array.
- Validation of RTK downregulation and downstream signaling inhibition (p-Akt, p-MEK1/2) via Western blot.
Main Results:
- Cabozantinib significantly decreased MBM cell viability in both culture models.
- In vitro cell migration was inhibited, and apoptosis was induced by cabozantinib treatment.
- Cabozantinib downregulated key phosphorylated RTKs (p-PDGF-Rα, p-IGF-1R, p-MERTK, p-DDR1) and inhibited downstream signaling pathways (p-Akt, p-MEK1/2).
Conclusions:
- Cabozantinib exhibits significant anti-tumor activity against MBM cells in vitro.
- The drug's mechanism involves the inhibition of multiple dysregulated RTKs and downstream signaling pathways.
- Further research is warranted to determine the therapeutic potential of cabozantinib for MBM.
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