Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications
Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications
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DOI：
10.1158/1535-7163.mct-15-0758
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发表时间：
2016-04-01
影响因子：
5.7
通讯作者：
Galvani, Arturo
中科院分区：
文献类型：
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作者：
Ardini, Elena;Menichincheri, Maria;Galvani, Arturo
由染色体重排引起的活化ALK和ROS 1酪氨酸激酶发生在非小细胞肺癌（NSCLC）亚组以及其他肿瘤类型中，其作为可操作靶点的致癌相关性已通过选择性激酶抑制剂（如克唑替尼、塞瑞替尼和阿来替尼）的疗效得到证实。最近，在NSCLC、结直肠癌、胶质母细胞瘤和Spitzoid黑色素瘤中描述了TRK激酶的低频重排。恩曲替尼的发现和临床前表征在本文中报道，恩曲替尼是ALK、ROS 1以及重要的TRK家族激酶的新型有效抑制剂，其显示出治疗携带这些蛋白质的致癌形式的肿瘤的前景。对200多种人类肿瘤细胞系的增殖分析表明，恩曲替尼在体外对依赖于药物药理学靶点的细胞系具有非常强的抑制作用。对荷瘤小鼠口服恩曲替尼可诱导相关人类异种移植肿瘤消退，包括TRKA依赖性结直肠癌KM 12、ROS 1驱动的肿瘤和几种不同组织来源的ALK依赖性模型，包括脑局部肺癌转移模型。Entrectinib目前在I/II期临床试验中显示出很大的前景，包括首次记录的在结直肠癌和NSCLC中对TRK抑制剂的客观反应。因此，该药物可能适用于治疗几种分子定义的癌症，特别是TRK依赖性肿瘤，目前还没有批准的药物。(C)2016年AACR。
Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. (C) 2016 AACR.