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Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors

Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosp...

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Autores principales: Nymark Aasen, Synnøve, Parajuli, Himalaya, Hoang, Tuyen, Feng, Zichao, Stokke, Krister, Wang, Jiwei, Roy, Kislay, Bjerkvig, Rolf, Knappskog, Stian, Thorsen, Frits
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747502/
https://www.ncbi.nlm.nih.gov/pubmed/31470659
http://dx.doi.org/10.3390/ijms20174235
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author Nymark Aasen, Synnøve
Parajuli, Himalaya
Hoang, Tuyen
Feng, Zichao
Stokke, Krister
Wang, Jiwei
Roy, Kislay
Bjerkvig, Rolf
Knappskog, Stian
Thorsen, Frits
author_facet Nymark Aasen, Synnøve
Parajuli, Himalaya
Hoang, Tuyen
Feng, Zichao
Stokke, Krister
Wang, Jiwei
Roy, Kislay
Bjerkvig, Rolf
Knappskog, Stian
Thorsen, Frits
author_sort Nymark Aasen, Synnøve
collection PubMed
description Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.
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spelling pubmed-67475022019-09-27 Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors Nymark Aasen, Synnøve Parajuli, Himalaya Hoang, Tuyen Feng, Zichao Stokke, Krister Wang, Jiwei Roy, Kislay Bjerkvig, Rolf Knappskog, Stian Thorsen, Frits Int J Mol Sci Article Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases. MDPI 2019-08-29 /pmc/articles/PMC6747502/ /pubmed/31470659 http://dx.doi.org/10.3390/ijms20174235 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nymark Aasen, Synnøve
Parajuli, Himalaya
Hoang, Tuyen
Feng, Zichao
Stokke, Krister
Wang, Jiwei
Roy, Kislay
Bjerkvig, Rolf
Knappskog, Stian
Thorsen, Frits
Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title_full Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title_fullStr Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title_full_unstemmed Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title_short Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
title_sort effective treatment of metastatic melanoma by combining mapk and pi3k signaling pathway inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747502/
https://www.ncbi.nlm.nih.gov/pubmed/31470659
http://dx.doi.org/10.3390/ijms20174235
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