A secondary RET mutation in the activation loop conferring resistance to vandetanib.
A secondary RET mutation in the activation loop conferring resistance to vandetanib.
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DOI：
10.1038/s41467-018-02994-7
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发表时间：
2018-02-12
影响因子：
16.6
通讯作者：
Goto K
中科院分区：
文献类型：
--
作者：
Nakaoku T;Kohno T;Araki M;Niho S;Chauhan R;Knowles PP;Tsuchihara K;Matsumoto S;Shimada Y;Mimaki S;Ishii G;Ichikawa H;Nagatoishi S;Tsumoto K;Okuno Y;Yoh K;McDonald NQ;Goto K
对凡德他尼（一种I型RET激酶抑制剂）的耐药发生在一名携带CCDC 6-RET融合的转移性肺腺癌患者中，该患者最初表现出对治疗的反应。耐药肿瘤获得了继发性突变，导致RET激酶结构域激活环中密码子904处丝氨酸取代为苯丙氨酸。S904 F突变通过增加RET激酶的ATP亲和力和自磷酸化活性赋予对凡德他尼的耐药性。通过热位移测定，在体外也观察到S904 F突变体与药物的相互作用减少。S904 F突变体的晶体结构揭示了F904周围的小疏水核心，可能通过稳定活性构象异构体来增强基础激酶活性。我们的研究结果表明，激酶结构域激活环中的错义突变能够通过变构效应增加激酶活性并赋予耐药性。肺癌对RET酪氨酸激酶抑制剂的获得性耐药机制在很大程度上是未知的。在这里，作者报告了一名肺腺癌患者，该患者在RET激酶（S904 F）中携带CCDC 6-RET突变，通过增加RET激酶的ATP亲和力和自磷酸化活性导致对激酶抑制剂凡德他尼的耐药性。
Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects. Mechanisms of acquired resistance to RET tyrosine kinase inhibitors in lung cancers are largely unknown. Here, the authors report in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
82.9
作者：
Kohno T;Ichikawa H;Totoki Y;Yasuda K;Hiramoto M;Nammo T;Sakamoto H;Tsuta K;Furuta K;Shimada Y;Iwakawa R;Ogiwara H;Oike T;Enari M;Schetter AJ;Okayama H;Haugen A;Skaug V;Chiku S;Yamanaka I;Arai Y;Watanabe S;Sekine I;Ogawa S;Harris CC;Tsuda H;Yoshida T;Yokota J;Shibata T
通讯作者：
Shibata T
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH