Patani, H, Bunney, TD, Thiyagarajan, N et al. (14 more authors) (2016) Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use. Oncotarget, 7 (17). pp. 24252-24268. ISSN 1949-2553
Abstract
Frequent genetic alterations discovered in FGFRs and evidence implicating some as drivers in diverse tumors has been accompanied by rapid progress in targeting FGFRs for anticancer treatments. Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options. We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of point-mutations reported in this domain. We reinforce the importance of N540K and K650E and establish that not all highly activating mutations (for example R669G) occur at high-frequency and conversely, that some “hotspots” may not be linked to activation. Further structural characterization consolidates a mechanistic view of FGFR kinase activation and extends insights into drug binding. Importantly, using several inhibitors of particular clinical interest (AZD4547, BGJ398, TKI258, JNJ42756493 and AP24534), we find that some activating mutations (including different replacements of the same residue) result in distinct changes in their efficacy. Considering that there is no approved inhibitor for anticancer treatments based on FGFR-targeting, this information will be immediately translatable to ongoing clinical trials.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2016 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY 3.0) |
Keywords: | precision medicine; cancer mutations; receptor tyrosine kinases; small molecule inhibitors; resistance |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Section of Experimental Oncology (Leeds) |
Funding Information: | Funder Grant number Yorkshire Cancer Research L367 Yorkshire Cancer Research L376PA |
Depositing User: | Symplectic Publications |
Date Deposited: | 09 Mar 2016 14:14 |
Last Modified: | 12 Apr 2017 17:41 |
Published Version: | https://dx.doi.org/10.18632/oncotarget.8132 |
Status: | Published |
Publisher: | Impact Journals |
Identification Number: | 10.18632/oncotarget.8132 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:95753 |