Cabozantinib inhibits melanoma brain metastasis in vitro

Abstract

Background Melanoma is one of the cancer types that have high potential to metastasise to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extra-cranial melanoma. However, few patients with melanoma brain metastases (MBM) respond effectively to recent treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved by FDA for treatment of renal cell carcinoma, medullary thyroid cancer and hepatocellular carcinoma. The drug also targets several of the proteins which are known to be dysregulated in melanomas and may therefore have a potential role in melanoma treatment. In this study, we investigated the effect of cabozantinib on MBM cell growth and migration in vitro, and further identified its associated molecular components. Methods The anti-tumour activity of cabozantinib was investigated on three human MBM cell lines (H1, H3, H10) developed in our laboratory, through monolayer cell viability assays, tumoursphere experiments, cell migration assays, flow cytometry and caspase 3/7 apoptosis assays, RTK array screening and western blots (WB) to validate the array findings. Results Cabozantinib treatment decreased the viability of MBM cell lines both when grown in monolayer cultures and as tumour 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 MBM cells after cabozantinib treatment. These results were validated with WB. Further, WB showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Conclusions For the first time, we show that cabozantinib effectively inhibits viability, growth and migration of MBM cells in vitro. Moreover, the drug induces apoptosis and downregulates the p-RTK p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 in MBM cells. Further in vivo experiments are needed to bring cabozantinib forward as a potential, adjuvant treatment of patients with MBM.