Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways

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 therap...

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Autores principales:	Trond Are Mannsåker, Tuyen Hoang, Synnøve Nymark Aasen, Ole Vidhammer Bjørnstad, Himalaya Parajuli, Terje Sundstrøm, Frits Alan Thorsen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	brain metastasis melanoma cabozantinib apoptosis PDGF-Rα IGF-1R Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/330126f1f5544c78b5d42641ad544f21
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spelling	oai:doaj.org-article:330126f1f5544c78b5d42641ad544f212021-11-25T17:55:10ZCabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways10.3390/ijms2222122961422-00671661-6596https://doaj.org/article/330126f1f5544c78b5d42641ad544f212021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12296https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Melanomas 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.Trond Are MannsåkerTuyen HoangSynnøve Nymark AasenOle Vidhammer BjørnstadHimalaya ParajuliTerje SundstrømFrits Alan ThorsenMDPI AGarticlebrain metastasismelanomacabozantinibapoptosisPDGF-RαIGF-1RBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12296, p 12296 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain metastasis melanoma cabozantinib apoptosis PDGF-Rα IGF-1R Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	brain metastasis melanoma cabozantinib apoptosis PDGF-Rα IGF-1R Biology (General) QH301-705.5 Chemistry QD1-999 Trond Are Mannsåker Tuyen Hoang Synnøve Nymark Aasen Ole Vidhammer Bjørnstad Himalaya Parajuli Terje Sundstrøm Frits Alan Thorsen Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
description	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.
format	article
author	Trond Are Mannsåker Tuyen Hoang Synnøve Nymark Aasen Ole Vidhammer Bjørnstad Himalaya Parajuli Terje Sundstrøm Frits Alan Thorsen
author_facet	Trond Are Mannsåker Tuyen Hoang Synnøve Nymark Aasen Ole Vidhammer Bjørnstad Himalaya Parajuli Terje Sundstrøm Frits Alan Thorsen
author_sort	Trond Are Mannsåker
title	Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
title_short	Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
title_full	Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
title_fullStr	Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
title_full_unstemmed	Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways
title_sort	cabozantinib is effective in melanoma brain metastasis cell lines and affects key signaling pathways
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/330126f1f5544c78b5d42641ad544f21
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Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways

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