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Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing
Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signaling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435825/ https://www.ncbi.nlm.nih.gov/pubmed/25971842 http://dx.doi.org/10.1038/ncomms8103 |
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author | Salton, Maayan Kasprzak, Wojciech K. Voss, Ty Shapiro, Bruce A. Poulikakos, Poulikos I. Misteli, Tom |
author_facet | Salton, Maayan Kasprzak, Wojciech K. Voss, Ty Shapiro, Bruce A. Poulikakos, Poulikos I. Misteli, Tom |
author_sort | Salton, Maayan |
collection | PubMed |
description | Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signaling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumors. However, patients rapidly develop resistance to vemurafenib treatment. One resistance mechanism is the emergence of BRAF alternative splicing isoforms leading to elimination of the RAS-binding domain. Here we identify interference with pre-mRNA splicing as a mechanism to combat vemurafenib resistance. We find that small molecule pre-mRNA splicing modulators reduce BRAF3-9 production and limit in-vitro cell growth of vemurafenib-resistant cells. In xenograft models, interference with pre-mRNA splicing prevents tumor formation and slows growth of vemurafenib-resistant tumors. Our results identify an intronic mutation as a molecular basis for RNA splicing-mediated RAF inhibitor resistance and we identify pre-mRNA splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma. |
format | Online Article Text |
id | pubmed-4435825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-44358252015-11-14 Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing Salton, Maayan Kasprzak, Wojciech K. Voss, Ty Shapiro, Bruce A. Poulikakos, Poulikos I. Misteli, Tom Nat Commun Article Mutations in the serine/threonine kinase BRAF are found in more than 60% of melanomas. The most prevalent melanoma mutation is BRAF(V600E), which constitutively activates downstream MAPK signaling. Vemurafenib is a potent RAF kinase inhibitor with remarkable clinical activity in BRAF(V600E)-positive melanoma tumors. However, patients rapidly develop resistance to vemurafenib treatment. One resistance mechanism is the emergence of BRAF alternative splicing isoforms leading to elimination of the RAS-binding domain. Here we identify interference with pre-mRNA splicing as a mechanism to combat vemurafenib resistance. We find that small molecule pre-mRNA splicing modulators reduce BRAF3-9 production and limit in-vitro cell growth of vemurafenib-resistant cells. In xenograft models, interference with pre-mRNA splicing prevents tumor formation and slows growth of vemurafenib-resistant tumors. Our results identify an intronic mutation as a molecular basis for RNA splicing-mediated RAF inhibitor resistance and we identify pre-mRNA splicing interference as a potential therapeutic strategy for drug resistance in BRAF melanoma. 2015-05-14 /pmc/articles/PMC4435825/ /pubmed/25971842 http://dx.doi.org/10.1038/ncomms8103 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Salton, Maayan Kasprzak, Wojciech K. Voss, Ty Shapiro, Bruce A. Poulikakos, Poulikos I. Misteli, Tom Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title | Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title_full | Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title_fullStr | Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title_full_unstemmed | Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title_short | Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing |
title_sort | inhibition of vemurafenib-resistant melanoma by interference with pre-mrna splicing |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435825/ https://www.ncbi.nlm.nih.gov/pubmed/25971842 http://dx.doi.org/10.1038/ncomms8103 |
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