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Targeting the Raf kinases in human cancer: the Raf dimer dilemma

The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alteratio...

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Detalles Bibliográficos
Autores principales: Durrant, David E, Morrison, Deborah K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765234/
https://www.ncbi.nlm.nih.gov/pubmed/29235562
http://dx.doi.org/10.1038/bjc.2017.399
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author Durrant, David E
Morrison, Deborah K
author_facet Durrant, David E
Morrison, Deborah K
author_sort Durrant, David E
collection PubMed
description The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In particular, issues related to the dimerisation of the Raf kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. Here, we will review the importance of Raf dimerisation in cell signalling as well as its effects on Raf inhibitor therapy, and we will present the new strategies that are being pursued to overcome the ‘Raf Dimer Dilemma’.
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spelling pubmed-57652342018-01-16 Targeting the Raf kinases in human cancer: the Raf dimer dilemma Durrant, David E Morrison, Deborah K Br J Cancer Minireview The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In particular, issues related to the dimerisation of the Raf kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. Here, we will review the importance of Raf dimerisation in cell signalling as well as its effects on Raf inhibitor therapy, and we will present the new strategies that are being pursued to overcome the ‘Raf Dimer Dilemma’. Nature Publishing Group 2018-01 2017-12-14 /pmc/articles/PMC5765234/ /pubmed/29235562 http://dx.doi.org/10.1038/bjc.2017.399 Text en Copyright © 2018 The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Minireview
Durrant, David E
Morrison, Deborah K
Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title_full Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title_fullStr Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title_full_unstemmed Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title_short Targeting the Raf kinases in human cancer: the Raf dimer dilemma
title_sort targeting the raf kinases in human cancer: the raf dimer dilemma
topic Minireview
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765234/
https://www.ncbi.nlm.nih.gov/pubmed/29235562
http://dx.doi.org/10.1038/bjc.2017.399
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