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j.celrep.2021.108876.pdf | 6.41 MB | Adobe PDF | 見る/開く |
タイトル: | Paradoxical activation of c-Src as a drug-resistant mechanism |
著者: | Higuchi, Makio Ishiyama, Kenichi Maruoka, Masahiro ![]() ![]() ![]() Kanamori, Ryosuke Takaori-Kondo, Akifumi Watanabe, Naoki ![]() ![]() ![]() |
著者名の別形: | 樋口, 牧郎 石山, 賢一 圓岡, 真宏 高折, 晃史 渡邊, 直樹 |
キーワード: | c-Src FAK kinase inhibitor drug resistance anchorage-dependent signaling paradoxical activation allosteric effects |
発行日: | 23-Mar-2021 |
出版者: | Elsevier BV |
誌名: | Cell Reports |
巻: | 34 |
号: | 12 |
論文番号: | 108876 |
抄録: | ATP-competitive inhibitors have been developed as promising anti-cancer agents. However, drug-resistance frequently occurs, and the underlying mechanisms are not fully understood. Here, we show that the activation of c-Src and its downstream phosphorylation cascade can be paradoxically induced by Src-targeted and RTK-targeted kinase inhibitors. We reveal that inhibitor binding induces a conformational change in c-Src, leading to the association of the active form c-Src with focal adhesion kinase (FAK). Reduction of the inhibitor concentration results in the dissociation of inhibitors from the c-Src-FAK complex, which allows c-Src to phosphorylate FAK and initiate FAK-Grb2-mediated Erk signaling. Furthermore, a drug-resistant mutation in c-Src, which reduces the affinity of inhibitors for c-Src, converts Src inhibitors into facilitators of cell proliferation by enhancing the phosphorylation of FAK and Erk in c-Src-mutated cells. Our data thus reveal paradoxical enhancement of cell growth evoked by target-based kinase inhibitors, providing potentially important clues for the future development of effective and safe cancer treatment. |
記述: | 抗がん剤抵抗性の新規メカニズムの解明 --薬剤抵抗性がん細胞は抗がん剤により増殖する--. 京都大学プレスリリース. 2021-03-25. |
著作権等: | © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
URI: | http://hdl.handle.net/2433/262322 |
DOI(出版社版): | 10.1016/j.celrep.2021.108876 |
PubMed ID: | 33761359 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2021-03-25 |
出現コレクション: | 学術雑誌掲載論文等 |
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