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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2018
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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’. |
format | Online Article Text |
id | pubmed-5765234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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