TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours

Yurina Saito, Tsuyoshi Takahashi, Yuuki Obata, Toshirou Nishida, Shuichi Ohkubo, Fumio Nakagawa, Satoshi Serada, Minoru Fujimoto, Tomoharu Ohkawara, Takahiko Nishigaki, Takahito Sugase, Masahiro Koh, Tomo Ishida, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Kiyokazu Nakajima, Makoto Yamasaki, Seiichi HirotaTetsuji Naka, Masaki Mori, Yuichiro Doki

研究成果: ジャーナルへの寄稿記事

抜粋

Background: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. Methods: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. Results: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. Conclusion: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

元の言語英語
ジャーナルBritish journal of cancer
DOI
出版物ステータス受理済み/印刷中 - 1 1 2019

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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