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Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma
Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase pr...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445818/ https://www.ncbi.nlm.nih.gov/pubmed/34304249 http://dx.doi.org/10.1038/s41388-021-01911-5 |
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author | Wang, Beike Zhang, Wei Zhang, Gao Kwong, Lawrence Lu, Hezhe Tan, Jiufeng Sadek, Norah Xiao, Min Zhang, Jie Labrie, Marilyne Randell, Sergio Beroard, Aurelie Sugarman, Eric Rebecca, Vito W. Wei, Zhi Lu, Yiling Mills, Gordon B. Field, Jeffrey Villanueva, Jessie Xu, Xiaowei Herlyn, Meenhard Guo, Wei |
author_facet | Wang, Beike Zhang, Wei Zhang, Gao Kwong, Lawrence Lu, Hezhe Tan, Jiufeng Sadek, Norah Xiao, Min Zhang, Jie Labrie, Marilyne Randell, Sergio Beroard, Aurelie Sugarman, Eric Rebecca, Vito W. Wei, Zhi Lu, Yiling Mills, Gordon B. Field, Jeffrey Villanueva, Jessie Xu, Xiaowei Herlyn, Meenhard Guo, Wei |
author_sort | Wang, Beike |
collection | PubMed |
description | Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma. |
format | Online Article Text |
id | pubmed-8445818 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84458182021-10-01 Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma Wang, Beike Zhang, Wei Zhang, Gao Kwong, Lawrence Lu, Hezhe Tan, Jiufeng Sadek, Norah Xiao, Min Zhang, Jie Labrie, Marilyne Randell, Sergio Beroard, Aurelie Sugarman, Eric Rebecca, Vito W. Wei, Zhi Lu, Yiling Mills, Gordon B. Field, Jeffrey Villanueva, Jessie Xu, Xiaowei Herlyn, Meenhard Guo, Wei Oncogene Article Targeting MAPK pathway using a combination of BRAF and MEK inhibitors is an efficient strategy to treat melanoma harboring BRAF-mutation. The development of acquired resistance is inevitable due to the signaling pathway rewiring. Combining western blotting, immunohistochemistry, and reverse phase protein array (RPPA), we aim to understanding the role of the mTORC1 signaling pathway, a center node of intracellular signaling network, in mediating drug resistance of BRAF-mutant melanoma to the combination of BRAF inhibitor (BRAFi) and MEK inhibitor (MEKi) therapy. The mTORC1 signaling pathway is initially suppressed by BRAFi and MEKi combination in melanoma but rebounds overtime after tumors acquire resistance to the combination therapy (CR) as assayed in cultured cells and PDX models. In vitro experiments showed that a subset of CR melanoma cells was sensitive to mTORC1 inhibition. The mTOR inhibitors, rapamycin and NVP-BEZ235, induced cell cycle arrest and apoptosis in CR cell lines. As a proof-of-principle, we demonstrated that rapamycin and NVP-BEZ235 treatment reduced tumor growth in CR xenograft models. Mechanistically, AKT or ERK contributes to the activation of mTORC1 in CR cells, depending on PTEN status of these cells. Our study reveals that mTOR activation is essential for drug resistance of melanoma to MAPK inhibitors, and provides insight into the rewiring of the signaling networks in CR melanoma. Nature Publishing Group UK 2021-07-24 2021 /pmc/articles/PMC8445818/ /pubmed/34304249 http://dx.doi.org/10.1038/s41388-021-01911-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wang, Beike Zhang, Wei Zhang, Gao Kwong, Lawrence Lu, Hezhe Tan, Jiufeng Sadek, Norah Xiao, Min Zhang, Jie Labrie, Marilyne Randell, Sergio Beroard, Aurelie Sugarman, Eric Rebecca, Vito W. Wei, Zhi Lu, Yiling Mills, Gordon B. Field, Jeffrey Villanueva, Jessie Xu, Xiaowei Herlyn, Meenhard Guo, Wei Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title | Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title_full | Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title_fullStr | Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title_full_unstemmed | Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title_short | Targeting mTOR signaling overcomes acquired resistance to combined BRAF and MEK inhibition in BRAF-mutant melanoma |
title_sort | targeting mtor signaling overcomes acquired resistance to combined braf and mek inhibition in braf-mutant melanoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445818/ https://www.ncbi.nlm.nih.gov/pubmed/34304249 http://dx.doi.org/10.1038/s41388-021-01911-5 |
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