Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.
Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use.
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DOI：
10.18632/oncotarget.8132
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Katan M
中科院分区：
文献类型：
--
作者：
Patani H;Bunney TD;Thiyagarajan N;Norman RA;Ogg D;Breed J;Ashford P;Potterton A;Edwards M;Williams SV;Thomson GS;Pang CS;Knowles MA;Breeze AL;Orengo C;Phillips C;Katan M
在FGFR中发现的频繁遗传变化，证据隐含了一些潜水肿瘤的驱动因素是通过靶向FGFR来靶向抗癌治疗方面的快速进步。数据和治疗方案。 R669G出现在高频上，相反，某些“热点”可能与进一步的结构表征相关。 AZD4547，BGJ-398，TKI258，JNJ42756493和AP24534），我们发现某些激活突变（包括同一住所的不同替换）会导致其效率的明显变化。针对性，此信息将立即转化为正在进行的临床试验。
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, BGJ-398, 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.
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DOI：
10.1038/nrm3528
发表时间：
2013-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
11.5
作者：
Brooks, A. Nigel;Kilgour, Elaine;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
9.8
作者：
Bellus, GA;Spector, EB;Francomano, CA
通讯作者：
Francomano, CA
致病性 FGF 受体 3 突变对 a 环酪氨酸磷酸化的结构模拟。
影响因子：
5.7
作者：
Huang, Zhifeng;Chen, Huaibin;Blais, Steven;Neubert, Thomas A.;Li, Xiaokun;Mohammadi, Moosa
通讯作者：
Mohammadi, Moosa
影响因子：
11.1
作者：
Bunney, Tom D.;Wan, Shunzhou;Thiyagarajan, Nethaji;Sutto, Ludovico;Williams, Sarah V.;Ashford, Paul;Koss, Hans;Knowles, Margaret A.;Gervasio, Francesco L.;Coveney, Peter V.;Katan, Matilda
通讯作者：
Katan, Matilda