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  3. A secondary RET mutation in the activation loop conferring resistance to vandetanib

A secondary RET mutation in the activation loop conferring resistance to vandetanib

  • Nat Commun. 2018 Feb 12;9(1):625. doi: 10.1038/s41467-018-02994-7.
Takashi Nakaoku 1,  Takashi Kohno 2 3,  Mitsugu Araki 4 5,  Seiji Niho 6,  Rakhee Chauhan 7,  Phillip P Knowles 7,  Katsuya Tsuchihara 8,  Shingo Matsumoto 8 6,  Yoko Shimada 1,  Sachiyo Mimaki 8,  Genichiro Ishii 9,  Hitoshi Ichikawa 8,  Satoru Nagatoishi 10,  Kouhei Tsumoto 10,  Yasushi Okuno 5,  Kiyotaka Yoh 6,  Neil Q McDonald 7 11,  Koichi Goto 6
Affiliations

Affiliations

  • 1 Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
  • 2 Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan. [email protected].
  • 3 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan. [email protected].
  • 4 Advanced Institute for Computational Science, RIKEN, 7-1-26 Minatojima-minami-machi, Chuo-ku, Kobe-city, Hyogo, 6500047, Japan.
  • 5 Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Kyoto-city, Kyoto, 6068507, Japan.
  • 6 Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-city, Chiba, 2778577, Japan.
  • 7 Signaling and Structural Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
  • 8 Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
  • 9 Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, 2778577, Japan.
  • 10 Medical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo, 1088639, Japan.
  • 11 Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London, WC1E 7HX, UK.
PMID: 29434222 DOI: 10.1038/s41467-018-02994-7
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.

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Products
  • Cat. No.
    Product Name
    Description
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  • HY-P10044
    KinaseSubstrate