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

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...

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Autores principales: Nakaoku, Takashi, Kohno, Takashi, Araki, Mitsugu, Niho, Seiji, Chauhan, Rakhee, Knowles, Phillip P., Tsuchihara, Katsuya, Matsumoto, Shingo, Shimada, Yoko, Mimaki, Sachiyo, Ishii, Genichiro, Ichikawa, Hitoshi, Nagatoishi, Satoru, Tsumoto, Kouhei, Okuno, Yasushi, Yoh, Kiyotaka, McDonald, Neil Q., Goto, Koichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809600/
https://www.ncbi.nlm.nih.gov/pubmed/29434222
http://dx.doi.org/10.1038/s41467-018-02994-7
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author Nakaoku, Takashi
Kohno, Takashi
Araki, Mitsugu
Niho, Seiji
Chauhan, Rakhee
Knowles, Phillip P.
Tsuchihara, Katsuya
Matsumoto, Shingo
Shimada, Yoko
Mimaki, Sachiyo
Ishii, Genichiro
Ichikawa, Hitoshi
Nagatoishi, Satoru
Tsumoto, Kouhei
Okuno, Yasushi
Yoh, Kiyotaka
McDonald, Neil Q.
Goto, Koichi
author_facet Nakaoku, Takashi
Kohno, Takashi
Araki, Mitsugu
Niho, Seiji
Chauhan, Rakhee
Knowles, Phillip P.
Tsuchihara, Katsuya
Matsumoto, Shingo
Shimada, Yoko
Mimaki, Sachiyo
Ishii, Genichiro
Ichikawa, Hitoshi
Nagatoishi, Satoru
Tsumoto, Kouhei
Okuno, Yasushi
Yoh, Kiyotaka
McDonald, Neil Q.
Goto, Koichi
author_sort Nakaoku, Takashi
collection PubMed
description 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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spelling pubmed-58096002018-02-14 A secondary RET mutation in the activation loop conferring resistance to vandetanib Nakaoku, Takashi Kohno, Takashi Araki, Mitsugu Niho, Seiji Chauhan, Rakhee Knowles, Phillip P. Tsuchihara, Katsuya Matsumoto, Shingo Shimada, Yoko Mimaki, Sachiyo Ishii, Genichiro Ichikawa, Hitoshi Nagatoishi, Satoru Tsumoto, Kouhei Okuno, Yasushi Yoh, Kiyotaka McDonald, Neil Q. Goto, Koichi Nat Commun Article 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. Nature Publishing Group UK 2018-02-12 /pmc/articles/PMC5809600/ /pubmed/29434222 http://dx.doi.org/10.1038/s41467-018-02994-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Nakaoku, Takashi
Kohno, Takashi
Araki, Mitsugu
Niho, Seiji
Chauhan, Rakhee
Knowles, Phillip P.
Tsuchihara, Katsuya
Matsumoto, Shingo
Shimada, Yoko
Mimaki, Sachiyo
Ishii, Genichiro
Ichikawa, Hitoshi
Nagatoishi, Satoru
Tsumoto, Kouhei
Okuno, Yasushi
Yoh, Kiyotaka
McDonald, Neil Q.
Goto, Koichi
A secondary RET mutation in the activation loop conferring resistance to vandetanib
title A secondary RET mutation in the activation loop conferring resistance to vandetanib
title_full A secondary RET mutation in the activation loop conferring resistance to vandetanib
title_fullStr A secondary RET mutation in the activation loop conferring resistance to vandetanib
title_full_unstemmed A secondary RET mutation in the activation loop conferring resistance to vandetanib
title_short A secondary RET mutation in the activation loop conferring resistance to vandetanib
title_sort secondary ret mutation in the activation loop conferring resistance to vandetanib
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809600/
https://www.ncbi.nlm.nih.gov/pubmed/29434222
http://dx.doi.org/10.1038/s41467-018-02994-7
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