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BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly

Despite the great success of small molecule inhibitors in the treatment of patients with BRAF(V600E) mutated melanoma, the response to these drugs remains transient and patients eventually relapse within a few months, highlighting the need to develop novel combination therapies based on the understa...

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Autores principales: Frischknecht, Lukas, Britschgi, Christian, Galliker, Patricia, Christinat, Yann, Vichalkovski, Anton, Gstaiger, Matthias, Kovacs, Werner J., Krek, Wilhelm
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533289/
https://www.ncbi.nlm.nih.gov/pubmed/31123282
http://dx.doi.org/10.1038/s41598-019-44112-7
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author Frischknecht, Lukas
Britschgi, Christian
Galliker, Patricia
Christinat, Yann
Vichalkovski, Anton
Gstaiger, Matthias
Kovacs, Werner J.
Krek, Wilhelm
author_facet Frischknecht, Lukas
Britschgi, Christian
Galliker, Patricia
Christinat, Yann
Vichalkovski, Anton
Gstaiger, Matthias
Kovacs, Werner J.
Krek, Wilhelm
author_sort Frischknecht, Lukas
collection PubMed
description Despite the great success of small molecule inhibitors in the treatment of patients with BRAF(V600E) mutated melanoma, the response to these drugs remains transient and patients eventually relapse within a few months, highlighting the need to develop novel combination therapies based on the understanding of the molecular changes induced by BRAF(V600E) inhibitors. The acute inhibition of oncogenic signaling can rewire entire cellular signaling pathways and thereby create novel cancer cell vulnerabilities. Here, we demonstrate that inhibition of BRAF(V600E) oncogenic signaling in melanoma cell lines leads to destabilization of the large subunit of RNA polymerase II POLR2A (polymerase RNA II DNA-directed polypeptide A), thereby preventing its binding to the unconventional prefoldin RPB5 interactor (URI1) chaperone complex and the successful assembly of RNA polymerase II holoenzymes. Furthermore, in melanoma cell lines treated with mitogen-activated protein kinase (MAPK) inhibitors, α-amanitin, a specific and irreversible inhibitor of RNA polymerase II, induced massive apoptosis. Pre-treatment of melanoma cell lines with MAPK inhibitors significantly reduced IC50 values to α-amanitin, creating a state of collateral vulnerability similar to POLR2A hemizygous deletions. Thus, the development of melanoma specific α-amanitin antibody-drug conjugates could represent an interesting therapeutic approach for combination therapies with BRAF(V600E) inhibitors.
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spelling pubmed-65332892019-06-03 BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly Frischknecht, Lukas Britschgi, Christian Galliker, Patricia Christinat, Yann Vichalkovski, Anton Gstaiger, Matthias Kovacs, Werner J. Krek, Wilhelm Sci Rep Article Despite the great success of small molecule inhibitors in the treatment of patients with BRAF(V600E) mutated melanoma, the response to these drugs remains transient and patients eventually relapse within a few months, highlighting the need to develop novel combination therapies based on the understanding of the molecular changes induced by BRAF(V600E) inhibitors. The acute inhibition of oncogenic signaling can rewire entire cellular signaling pathways and thereby create novel cancer cell vulnerabilities. Here, we demonstrate that inhibition of BRAF(V600E) oncogenic signaling in melanoma cell lines leads to destabilization of the large subunit of RNA polymerase II POLR2A (polymerase RNA II DNA-directed polypeptide A), thereby preventing its binding to the unconventional prefoldin RPB5 interactor (URI1) chaperone complex and the successful assembly of RNA polymerase II holoenzymes. Furthermore, in melanoma cell lines treated with mitogen-activated protein kinase (MAPK) inhibitors, α-amanitin, a specific and irreversible inhibitor of RNA polymerase II, induced massive apoptosis. Pre-treatment of melanoma cell lines with MAPK inhibitors significantly reduced IC50 values to α-amanitin, creating a state of collateral vulnerability similar to POLR2A hemizygous deletions. Thus, the development of melanoma specific α-amanitin antibody-drug conjugates could represent an interesting therapeutic approach for combination therapies with BRAF(V600E) inhibitors. Nature Publishing Group UK 2019-05-23 /pmc/articles/PMC6533289/ /pubmed/31123282 http://dx.doi.org/10.1038/s41598-019-44112-7 Text en © The Author(s) 2019 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/.
spellingShingle Article
Frischknecht, Lukas
Britschgi, Christian
Galliker, Patricia
Christinat, Yann
Vichalkovski, Anton
Gstaiger, Matthias
Kovacs, Werner J.
Krek, Wilhelm
BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title_full BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title_fullStr BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title_full_unstemmed BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title_short BRAF inhibition sensitizes melanoma cells to α-amanitin via decreased RNA polymerase II assembly
title_sort braf inhibition sensitizes melanoma cells to α-amanitin via decreased rna polymerase ii assembly
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533289/
https://www.ncbi.nlm.nih.gov/pubmed/31123282
http://dx.doi.org/10.1038/s41598-019-44112-7
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