Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.
Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.
复制标题
癌症中的酪氨酸激酶基因融合：将机制转化为靶向疗法。
DOI：
10.1111/j.1582-4934.2011.01415.x
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发表时间：
2012-02
影响因子：
5.3
通讯作者：
Demoulin JB
中科院分区：
文献类型：
--
作者：
Medves S;Demoulin JB
酪氨酸激酶融合基因是一类重要的与白血病和实体瘤相关的癌基因。它们是由酪氨酸激酶基因的一个子集的易位和其他染色体重排产生的，包括ABL、PDGFRA、PDGFRB、FGFR 1、SYK、RET、JAK 2和ALK。本文结合近年来的研究成果，对这些融合基因的共同激活机制进行了综述。抑制结构域的强制寡聚化和失活是开启激酶结构域的两个关键过程。激活的酪氨酸激酶融合然后通过一系列转导级联信号，这在很大程度上是共享的。此外，融合伴侣提供了用于募集蛋白质的支架，所述蛋白质有助于信号传导、蛋白质稳定性、细胞定位和寡聚化。融合蛋白的表达水平是另一个关键参数。其转录受伴侣基因启动子控制，而翻译可能受miRNA调控。几种机制也阻止蛋白酶体和溶酶体降解癌蛋白，导致其在细胞中积累。腺苷-5 ′-三磷酸竞争剂（如伊马替尼）选择性抑制酪氨酸激酶活性是一项重大的治疗成功。伊马替尼诱导BCR-ABL或PDGFR融合阳性的白血病患者缓解。最近，克唑替尼在ALK融合的肺癌亚型中产生了有希望的结果。然而，在这两种情况下都报告了耐药性，部分原因是突变。为了解决这个问题，融合酪氨酸激酶激活的复杂机制建议了额外水平的治疗干预。新的方法包括变构抑制和干扰寡聚化或分子伴侣。
Tyrosine kinase fusion genes represent an important class of oncogenes associated with leukaemia and solid tumours. They are produced by translocations and other chromosomal rearrangements of a subset of tyrosine kinase genes, including ABL, PDGFRA, PDGFRB, FGFR1, SYK, RET, JAK2 and ALK. Based on recent findings, this review discusses the common mechanisms of activation of these fusion genes. Enforced oligomerization and inactivation of inhibitory domains are the two key processes that switch on the kinase domain. Activated tyrosine kinase fusions then signal via an array of transduction cascades, which are largely shared. In addition, the fusion partner provides a scaffold for the recruitment of proteins that contribute to signalling, protein stability, cellular localization and oligomerization. The expression level of the fusion protein is another critical parameter. Its transcription is controlled by the partner gene promoter, while translation may be regulated by miRNA. Several mechanisms also prevent the degradation of the oncoprotein by proteasomes and lysosomes, leading to its accumulation in cells. The selective inhibition of the tyrosine kinase activity by adenosine-5′-triphosphate competitors, such as imatinib, is a major therapeutic success. Imatinib induces remission in leukaemia patients that are positive for BCR-ABL or PDGFR fusions. Recently, crizotinib produced promising results in a subtype of lung cancers with ALK fusion. However, resistance was reported in both cases, partially due to mutations. To tackle this problem, additional levels of therapeutic interventions are suggested by the complex mechanisms of fusion tyrosine kinase activation. New approaches include allosteric inhibition and interfering with oligomerization or chaperones.
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影响因子：
3.3
作者：
Bell, CA;Tynan, JA;Donoghue, DJ
通讯作者：
Donoghue, DJ
DOI：
10.3324/haematol.2009.016345
发表时间：
2010-05-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Erben, Philipp;Gosenca, Darko;Reiter, Andreas
通讯作者：
Reiter, Andreas
影响因子：
11.4
作者：
Futami, M.;Hatano, T.;Tojo, A.
通讯作者：
Tojo, A.
影响因子：
8
作者：
Gandhi, M.;Dillon, L. W.;Wang, Y-H
通讯作者：
Wang, Y-H
影响因子：
50.3
作者：
Chan WW;Wise SC;Kaufman MD;Ahn YM;Ensinger CL;Haack T;Hood MM;Jones J;Lord JW;Lu WP;Miller D;Patt WC;Smith BD;Petillo PA;Rutkoski TJ;Telikepalli H;Vogeti L;Yao T;Chun L;Clark R;Evangelista P;Gavrilescu LC;Lazarides K;Zaleskas VM;Stewart LJ;Van Etten RA;Flynn DL
通讯作者：
Flynn DL