The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.,Nature Communications

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The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models.
Nature Communications ( IF 14.7 ) Pub Date : 2019-08-09 , DOI: 10.1038/s41467-019-11496-z
Ryohei Katayama ₁ , Bo Gong _{1,

2} , Noriko Togashi ₃ , Masaya Miyamoto ₃ , Masaki Kiga ₃ , Shiho Iwasaki ₃ , Yasuki Kamai ₃ , Yuichi Tominaga ₃ , Yasuyuki Takeda ₃ , Yoshiko Kagoshima ₃ , Yuki Shimizu _{1,

2} , Yosuke Seto ₁ , Tomoko Oh-Hara ₁ , Sumie Koike ₁ , Naoki Nakao ₄ , Hiroyuki Hanzawa ₄ , Kengo Watanabe ₃ , Satoshi Yoda _{5,

6} , Noriko Yanagitani ₇ , Aaron N Hata _{5,

6} , Alice T Shaw _{5,

6} , Makoto Nishio ₇ , Naoya Fujita _{1,

2} , Takeshi Isoyama ₃

Affiliation

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.

中文翻译：

新一代选择性ROS1 / NTRK抑制剂DS-6051b在临床前模型中克服了耐克唑替尼的ROS1-G2032R突变。

在大约1-2％的NSCLC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ROS1基因重排。克唑替尼是一种ALK / ROS1 / MET抑制剂，对ROS1重组肺癌非常有效，可用于临床。然而，克唑替尼耐药性是一个新兴问题，在克唑替尼难治性患者中已鉴定出几种耐药机制，例如继发激酶结构域突变（例如ROS1-G2032R）。在这里，我们在ROS1或NTRK重排的癌症的临床前模型中表征了一种新型的选择性ROS1 / NTRK抑制剂DS-6051b。DS-6051b在体外和体内均对野生型和G2032R突变型ROS1重排的癌症或NTRK重排的癌症均具有显着的生长抑制作用。

更新日期：2019-08-09

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