The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models
The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models
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DOI：
10.1038/s41467-019-11496-z
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发表时间：
2019-08-09
影响因子：
16.6
通讯作者：
Isoyama, Takeshi
中科院分区：
文献类型：
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作者：
Katayama, Ryohei;Gong, Bo;Isoyama, Takeshi
在大约1- 2%的非小细胞肺癌患者和其他几种癌症（例如胆管癌、胶质母细胞瘤或结直肠癌）中观察到了ROS 1基因重排。克唑替尼是一种ALK/ROS 1/MET抑制剂，对ROS 1重排的肺癌有很高的疗效，已被用于临床。然而，克唑替尼耐药是一个新出现的问题，并且几种耐药机制，如继发性激酶结构域突变（例如，ROS1-G2032R）。在这里，我们描述了一种新的选择性ROS 1/NTRK抑制剂DS-6051 b在ROS 1或NTRK重排癌症的临床前模型中的特征。DS-6051 b在体外和体内诱导野生型和G2032 R突变型ROS 1重排癌症或NTRK重排癌症的显著生长抑制。我们在此报告DS-6051 b可有效治疗临床前模型中的ROS 1或NTRK重排癌症，包括伴有继发激酶结构域突变的克唑替尼耐药ROS 1阳性癌症，尤其是对克唑替尼以及下一代ROS 1抑制剂劳拉替尼和恩曲替尼高度耐药的G2032 R突变。
ROS1 gene rearrangement was observed in around 1-2 % of NSCLC patients and in several other cancers such as cholangiocarcinoma, glioblastoma, or colorectal cancer. Crizotinib, an ALK/ROS1/MET inhibitor, is highly effective against ROS1-rearranged lung cancer and is used in clinic. However, crizotinib resistance is an emerging issue, and several resistance mechanisms, such as secondary kinase-domain mutations (e.g., ROS1-G2032R) have been identified in crizotinib-refractory patients. Here we characterize a new selective ROS1/NTRK inhibitor, DS-6051b, in preclinical models of ROS1- or NTRK-rearranged cancers. DS-6051b induces dramatic growth inhibition of both wild type and G2032R mutant ROS1-rearranged cancers or NTRK-rearranged cancers in vitro and in vivo. Here we report that DS-6051b is effective in treating ROS1- or NTRK-rearranged cancer in preclinical models, including crizotinib-resistant ROS1 positive cancer with secondary kinase domain mutations especially G2032R mutation which is highly resistant to crizotinib as well as lorlatinib and entrectinib, next generation ROS1 inhibitors.