癌におけるNADの代謝依存は,遺伝子増強と強化器の改造によって形成される
Sudhir Chowdhry1, Ciro Zanca1, Utkrisht Rajkumar2
1Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA, USA.
Nature
|April 26, 2019
まとめ
がん細胞の生存は組織型に依存し,特定のニコチナミドアデニンジヌクレオチド (NAD) 合成経路に依存する. この発見は治療の失敗を説明し,がん代謝を標的とした新しい精密腫瘍学戦略を導く.
科学分野:
- 腫瘍学
- 癌 代謝
- 分子生物学
背景:
- 精密腫瘍学は 標的薬と腫瘍の遺伝子型を合わせることを目的としています
- 癌の代謝失調をターゲットにすることは 重要な課題です
- ニコチナミドアデニンジヌクレオチド (NAD) の代謝は,がんで頻繁に変化する.
研究 の 目的:
- 癌細胞がNAD代謝経路に依存することを決定する組織文脈の役割を調査する.
- 異なる癌の種類におけるNAD経路の利用に関する実行可能な規則を特定する.
- NAD合成酵素を標的とする効果と限界を説明する.
主な方法:
- 19種類の腫瘍と2600種類の正常な組織を分析した
- NAD代謝の数学モデル化
- インビトロとインビボの実験的検証
主要な成果:
- 組織の文脈は,がん細胞が新生または救済NAD合成経路に依存することを決定する.
- NAPRT発現率が高い組織からの癌は,NAPRT増幅に依存しています.
- 低NAPRT発現組織からの腫瘍は,特定された増強剤による救済経路に依存しています.
- NAPRTの増幅は 薬学的に操作可能な脆弱性を生み出します
- NAMPT阻害剤耐性は,NMRK1に依存したNAD合成に関連しています.
結論:
- 組織の文脈は,がんにおけるNAD代謝経路依存性の重要な決定因子である.
- この研究は,特定のNAMPT阻害剤の失敗を説明しています.
- 発見は,NAD代謝を標的とした新しい文脈特有のがん治療の開発の枠組みを提供します.
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