The EML4-ALK oncogene: targeting an essential growth driver in human cancer.
The EML4-ALK oncogene: targeting an essential growth driver in human cancer.
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DOI：
10.2183/pjab.91.193
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Mano H
中科院分区：
文献类型：
--
作者：
Mano H
靶向必需的生长驱动因素代表了癌症治疗的理想方法。为了在临床标本中鉴定这些分子，我们开发了一种基于制备逆转录病毒cDNA表达文库的高灵敏度功能筛选系统。通过用焦点形成试验筛选这样的肺腺癌文库，我们发现了EML 4-ALK融合型癌基因。因此，一个小的染色体倒位导致微管相关蛋白EML 4的氨基末端部分与ALK（一种受体型蛋白酪氨酸激酶）的细胞内激酶结构域融合。由EML 4的二聚化基序介导的EML 4-ALK的组成型二聚化导致激酶活化。ALK激酶活性的特异性抑制剂已被开发为EML 4-ALK阳性肺癌的治疗药物，其中三种（克唑替尼、塞瑞替尼和阿来替尼）已被批准用于临床。alectinib的总体临床缓解率为93.5%，表明靶向基本生长驱动因子的药物可以成为癌症治疗的灵丹妙药。
Targeting of essential growth drivers represents an ideal approach to cancer treatment. To identify such molecules in clinical specimens, we developed a highly sensitive functional screening system based on the preparation of retroviral cDNA expression libraries. By screening such a library of lung adenocarcinoma with a focus formation assay, we discovered the EML4-ALK fusion-type oncogene. A small chromosomal inversion thus leads to fusion of the amino-terminal portion of the microtubule-associated protein EML4 to the intracellular kinase domain of ALK, a receptor-type protein tyrosine kinase. Constitutive dimerization of EML4-ALK mediated by a dimerization motif of EML4 results in kinase activation. Specific inhibitors of the kinase activity of ALK have been developed as therapeutic drugs for EML4-ALK–positive lung cancer, three of which (crizotinib, ceritinib, and alectinib) have already been approved for clinical use. An overall clinical response rate of 93.5% for alectinib has shown that agents that target essential growth drivers can become magic bullets for cancer treatment.