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, Genichiro Ishii, Hitoshi Ichikawa, Satoru Nagatoishi, Kouhei Tsumoto, Yasushi Okuno, Kiyotaka Yoh, Neil Q. McDonald and Koichi Goto
Additional contact information
Takashi Nakaoku: National Cancer Center Research Institute
Takashi Kohno: National Cancer Center Research Institute
Mitsugu Araki: RIKEN
Seiji Niho: National Cancer Center Hospital East
Rakhee Chauhan: The Francis Crick Institute
Phillip P. Knowles: The Francis Crick Institute
Katsuya Tsuchihara: National Cancer Center
Shingo Matsumoto: National Cancer Center
Yoko Shimada: National Cancer Center Research Institute
Sachiyo Mimaki: National Cancer Center
Genichiro Ishii: National Cancer Center
Hitoshi Ichikawa: National Cancer Center
Satoru Nagatoishi: The University of Tokyo
Kouhei Tsumoto: The University of Tokyo
Yasushi Okuno: Kyoto University
Kiyotaka Yoh: National Cancer Center Hospital East
Neil Q. McDonald: The Francis Crick Institute
Koichi Goto: National Cancer Center Hospital East

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-02994-7

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