Evidence map›Paper›PMID 29434222›Full record

ArticleNature communications2018

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

Takashi Nakaoku, Takashi Kohno, Mitsugu Araki, Seiji Niho, Rakhee Chauhan, Phillip P Knowles, Katsuya Tsuchihara, Shingo Matsumoto, Yoko Shimada, Sachiyo Mimaki and 8 more

Open access · goldAbstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.

0numbers the graph read from it
0cells of the map it votes in
58citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

58 citing papers in PubMed, 106 citations in OpenAlex.

  1. Article
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  9. Systemic Therapies for Advanced Medullary Thyroid Carcinoma.Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer · 2025
    Review
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  13. Cancers · 2023
    Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 6 institutions in 2 countries.

Takashi NakaokuDivision of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Takashi KohnoDivision of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan. tkkohno@ncc.go.jp.
Mitsugu ArakiAdvanced Institute for Computational Science, RIKEN, 7-1-26 Minatojima-minami-machi, Chuo-ku, Kobe-city, Hyogo, 6500047, Japan.
Seiji NihoDepartment of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-city, Chiba, 2778577, Japan.
Rakhee ChauhanSignaling and Structural Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
Phillip P KnowlesSignaling and Structural Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
Katsuya TsuchiharaDivision of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Shingo MatsumotoDivision of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Yoko ShimadaDivision of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Sachiyo MimakiDivision of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Genichiro IshiiDivision of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa-City, Chiba, 2778577, Japan.
Hitoshi IchikawaDivision of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Satoru NagatoishiMedical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo, 1088639, Japan.
Kouhei TsumotoMedical Proteomics Laboratory, Institute of Medical Science, The University of Tokyo, 4-6-1, Shiroganedai, Minato-ku, Tokyo, 1088639, Japan.
Yasushi OkunoDepartment of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Kyoto-city, Kyoto, 6068507, Japan.
Kiyotaka YohDepartment of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-city, Chiba, 2778577, Japan.
Neil Q McDonaldSignaling and Structural Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK.
Koichi GotoDepartment of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-city, Chiba, 2778577, Japan.
National Cancer Centre Japan · JPNational Cancer Center Hospital East · JPThe Francis Crick Institute · GBThe University of Tokyo · JPKyoto University · JPRIKEN Center for Computational Science · JP

Funding

Selective RET Kinase and Its Mutant Inhibitors for the Treatment of Medullary Thyroid CancerR01CA197178 · NCI · UNIV OF ARKANSAS FOR MED SCIS · PI LI, HONG-YU, MCDONALD, NEIL · 2015 to 2019
$1.5M
NCI NIH HHS R01 CA197178Wellcome Trust
6 · The paper itself

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.

Indexed as

Mutation, MissenseAdenocarcinomaCell Line, TumorCell SurvivalDrug Resistance, NeoplasmFemaleHumansLung NeoplasmsMiddle AgedPiperidinesProto-Oncogene Proteins c-retQuinazolinesPiperidinesProto-Oncogene Proteins c-retQuinazolinesvandetanib

Identifiers

PMID29434222
PMCPMC5809600
OpenAlexW2792649904

What OpenQuestion holds

Textmetadata
LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.