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
Division of Genome Biology, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
Nat Commun. 2018 Feb 12;9(1):625. doi: 10.1038/s41467-018-02994-7.
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.
一名患有转移性肺腺癌且携带CCDC6-RET融合基因的患者，最初对I型RET激酶抑制剂凡德他尼治疗有反应，但后来出现了耐药。耐药肿瘤获得了一个继发性突变，导致RET激酶结构域激活环中第904位密码子由丝氨酸突变为苯丙氨酸。S904F突变通过增加RET激酶的ATP亲和力和自身磷酸化活性，赋予对凡德他尼的耐药性。通过热位移分析在体外也观察到S904F突变体与药物的相互作用减少。S904F突变体的晶体结构显示F904周围有一个小的疏水核心，可能通过稳定活性构象来增强基础激酶活性。我们的研究结果表明，激酶结构域激活环中的错义突变能够增加激酶活性并通过变构效应赋予耐药性。
