Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Department of Neurosurgery, Haukeland University Hospital, Haukelandsveien 22, 5021 Bergen, Norway.
Int J Mol Sci. 2021 Nov 14;22(22):12296. doi: 10.3390/ijms222212296.
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.
黑色素瘤有很高的脑转移风险。近年来，靶向治疗和免疫治疗的进展改变了颅外黑色素瘤的治疗格局。然而，很少有脑转移黑色素瘤（MBM）患者对这些治疗有有效反应，因此需要新的治疗策略。卡博替尼是一种受体酪氨酸激酶（RTK）抑制剂，已被批准用于治疗非皮肤相关癌症。该药物针对的是已知在黑色素瘤中失调的几种蛋白质。使用三种人 MBM 细胞系研究了卡博替尼的抗肿瘤活性。卡博替尼治疗不仅降低了单层培养和肿瘤球体中所有细胞系的活力，还抑制了体外细胞迁移并诱导了细胞凋亡。在卡博替尼治疗后，MBM 细胞的 p-RTK 阵列中发现磷酸化的 RTKs p-PDGF-Rα、p-IGF-1R、p-MERTK 和 p-DDR1 下调。Western blot 验证了这些结果，并表明卡博替尼治疗抑制了 p-Akt 和 p-MEK 1/2。需要进一步的研究来阐明卡博替尼对 MBM 患者的治疗潜力。
