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

Takashi Nakaoku,Satoru Nagatoishi,Genichiro Ishii,Neil Q Mcdonald,Shingo Matsumoto,Katsuya Tsuchihara,Takashi Kohno,Koichi Goto,Sachiyo Mimaki,Seiji Niho,Kiyotaka Yoh,Kouhei Tsumoto,Phillip P Knowles,Rakhee Chauhan,Yoko Shimada,Mitsugu Araki,Hitoshi Ichikawa,Yasushi Okuno

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.

Highlights

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
Oncogenic ALK and ROS1 fusion-targeted therapy using type I tyrosine-kinase inhibitors (TKIs), which bind to the ATP-binding cleft of kinases, is highly effective in lung adenocarcinoma (LADC)[1,2]; such cancers inevitably acquire resistance to targeted therapies, which severely limits the efficacy of cancer treatments
The patient described was enrolled into our clinical trial[8], LURET (Lung Cancer with RET Rearrangement Study; clinical trial registration number: UMIN000010095, https://upload.umin.ac.jp/), which investigates the efficacy of vandetanib for the treatment of nonsmall cell lung cancer (NSCLC) with oncogenic RET fusion

Summary

Introduction

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 patient described was enrolled into our clinical trial[8], LURET (Lung Cancer with RET Rearrangement Study; clinical trial registration number: UMIN000010095, https://upload.umin.ac.jp/), which investigates the efficacy of vandetanib for the treatment of nonsmall cell lung cancer (NSCLC) with oncogenic RET fusion. In this trial, 19 RET fusion-positive cases were enrolled through genetic screening of 1536 patients, and 17 eligible cases showed a response rate of 53% and a progression-free survival period of 4–7 months[8]

Methods

Results

Conclusion