論文 - 詳細
| RRC ID | 58004 |
|---|---|
| 著者 | Katayama R, Gong B, Togashi N, Miyamoto M, Kiga M, Iwasaki S, Kamai Y, Tominaga Y, Takeda Y, Kagoshima Y, Shimizu Y, Seto Y, Oh-Hara T, Koike S, Nakao N, Hanzawa H, Watanabe K, Yoda S, Yanagitani N, Hata AN, Shaw AT, Nishio M, Fujita N, Isoyama T. |
| タイトル | The new-generation selective ROS1/NTRK inhibitor DS-6051b overcomes crizotinib resistant ROS1-G2032R mutation in preclinical models. |
| ジャーナル | Nat Commun |
| Abstract |
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. |
| 巻・号 | 10(1) |
| ページ | 3604 |
| 公開日 | 2019-8-9 |
| DOI | 10.1038/s41467-019-11496-z |
| PII | 10.1038/s41467-019-11496-z |
| PMID | 31399568 |
| PMC | PMC6688997 |
| MeSH | Aminopyridines Benzamides / pharmacology Carcinoma, Non-Small-Cell Lung / genetics Cell Line, Tumor Cell Survival / drug effects Crizotinib / pharmacology* Drug Development Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Humans Indazoles / pharmacology Lactams Lactams, Macrocyclic / pharmacology Lung Neoplasms / genetics Membrane Glycoproteins / antagonists & inhibitors* Mutation / drug effects Protein Kinase Inhibitors / pharmacology* Protein-Tyrosine Kinases / antagonists & inhibitors* Protein-Tyrosine Kinases / genetics Proto-Oncogene Proteins / antagonists & inhibitors* Proto-Oncogene Proteins / genetics Pyrazoles Receptor, trkB / antagonists & inhibitors* |
| IF | 12.121 |
| 引用数 | 9 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | News |
| 各媒体での言及数の合計 | 38 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3 |