Alectinib Shows Potent Antitumor Activity against RET-Rearranged Non-Small Cell Lung Cancer
Alectinib Shows Potent Antitumor Activity against RET-Rearranged Non-Small Cell Lung Cancer
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DOI：
10.1158/1535-7163.mct-14-0274
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发表时间：
2014-12-01
影响因子：
5.7
通讯作者：
Sakamoto, Hiroshi
中科院分区：
文献类型：
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作者：
Kodama, Tatsushi;Tsukaguchi, Toshiyuki;Sakamoto, Hiroshi
Alectinib/CH 5424802是一种已知的间变性淋巴瘤激酶（ALK）抑制剂，正在临床试验中评估其治疗ALK融合阳性非小细胞肺癌（NSCLC）的效果。最近，一些RET和ROS 1融合基因被认为是NSCLC中的驱动癌基因，并已成为抗肿瘤药物的分子靶点。本研究旨在通过检测alectinib抑制ALK以外激酶活性的能力，探索alectinib的其他靶向适应症。我们最新证实了alectinib通过抑制RET磷酸化抑制RET激酶活性和RET融合阳性细胞的生长。相比之下，与其他ALK/ROS 1抑制剂（如克唑替尼和LDK 378）不同，alectinib几乎不能抑制ROS 1激酶活性。它还在RET融合驱动的肿瘤小鼠模型中显示出抗肿瘤活性。此外，alectinib显示出对RET看门突变（RET V804 L和V804 M）的激酶抑制活性，并阻断由KIF 5 B-RET V804 L和V804 M驱动的细胞生长。我们的结果表明，alectinib对RET融合阳性肿瘤有效。因此，alectinib可能是RET融合阳性NSCLC患者的治疗选择。（C）2014年AACR。
Alectinib/CH5424802 is a known inhibitor of anaplastic lymphoma kinase (ALK) and is being evaluated in clinical trials for the treatment of ALK fusion-positive non-small cell lung cancer (NSCLC). Recently, some RET and ROS1 fusion genes have been implicated as driver oncogenes in NSCLC and have become molecular targets for antitumor agents. This study aims to explore additional target indications of alectinib by testing its ability to inhibit the activity of kinases other than ALK. We newly verified that alectinib inhibited RET kinase activity and the growth of RET fusion-positive cells by suppressing RET phosphorylation. In contrast, alectinib hardly inhibited ROS1 kinase activity unlike other ALK/ROS1 inhibitors such as crizotinib and LDK378. It also showed antitumor activity in mouse models of tumors driven by the RET fusion. In addition, alectinib showed kinase inhibitory activity against RET gatekeeper mutations (RET V804L and V804M) and blocked cell growth driven by the KIF5B-RET V804L and V804M. Our results suggest that alectinib is effective against RET fusion-positive tumors. Thus, alectinib might be a therapeutic option for patients with RET fusion-positive NSCLC. (C)2014 AACR.