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.
Highlights
Melanoma incidence rates are steadily increasing and over a third of patients with a metastatic disease have brain metastases at the time of diagnosis [1]
The phosphorylated receptor tyrosine kinase (RTK) p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the melanoma brain metastasis (MBM) cells after cabozantinib treatment
The results showed that cabozantinib treatment led to a reduced expression of several p-RTKs in H1 cells. pIGF-1R, p-MERTK and p-DDR1 displayed the most significant reduction whereas the pPDGF-Rα protein expression was not a significant decrease (Figure 5; Supplementary Figure S4)
Summary
Melanoma incidence rates are steadily increasing and over a third of patients with a metastatic disease have brain metastases at the time of diagnosis [1]. Around 40% of melanomas have a BRAF mutation, most frequently BRAFV600E [2]. BRAF inhibitors such as vemurafenib or dabrafenib have shown intracranial responses in most patients [3]. The responses are typically incomplete and short-lived due to intrinsic and extrinsic resistance mechanisms. Immunotherapies have increased melanoma survival but it remains difficult to predict responses [4]. The drug therapy of brain metastases is further hampered by a limited drug penetration beyond the blood–brain barrier (BBB) [5,6]
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