論文 - 詳細
| RRC ID | 50650 |
|---|---|
| 著者 | Nakaoku T, Kohno T, Araki M, Niho S, Chauhan R, Knowles PP, Tsuchihara K, Matsumoto S, Shimada Y, Mimaki S, Ishii G, Ichikawa H, Nagatoishi S, Tsumoto K, Okuno Y, Yoh K, McDonald NQ, Goto K. |
| タイトル | A secondary RET mutation in the activation loop conferring resistance to vandetanib. |
| ジャーナル | Nat Commun |
| Abstract |
Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with the drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects. |
| 巻・号 | 9(1) |
| ページ | 625 |
| 公開日 | 2018-2-12 |
| DOI | 10.1038/s41467-018-02994-7 |
| PII | 10.1038/s41467-018-02994-7 |
| PMID | 29434222 |
| PMC | PMC5809600 |
| MeSH | Adenocarcinoma / drug therapy Adenocarcinoma / genetics* Adenocarcinoma / pathology Cell Line, Tumor Cell Survival / drug effects Cell Survival / genetics Drug Resistance, Neoplasm / genetics* Female Humans Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Lung Neoplasms / pathology Middle Aged Mutation, Missense* Piperidines / pharmacology Piperidines / therapeutic use* Proto-Oncogene Proteins c-ret / antagonists & inhibitors Proto-Oncogene Proteins c-ret / genetics* Quinazolines / pharmacology Quinazolines / therapeutic use* |
| IF | 12.121 |
| 引用数 | 21 |
| リソース情報 | |
| ヒト・動物細胞 | WEHI-3B(RCB2853) |