EZH2-Aberrant Solid Tumorsの治療戦略としてエピジェネティック・クロスストークをターゲットにする
Xun Huang1, Juan Yan2, Min Zhang3
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China.
Cell
|September 18, 2018
まとめ
EZH2阻害剤の有効性を高めるには,エピジェネティック・クロストークとMAPK経路を標的とする必要があります. 組み合わせ治療は EZH2 変異性固体腫瘍に対して有望であり,治療結果を改善します.
科学分野:
- 腫瘍学
- エピジェネティクス
- 分子生物学
背景:
- 増強剤Zeste Homolog 2 (EZH2) 変異は,がんにおいて一般的であるが,EZH2阻害剤 (EZH2i) は,主に血液学的悪性腫瘍において,有効性が限られている.
- EZH2iに対する耐性メカニズムの理解は,効果的ながん治療法の開発に不可欠です.
研究 の 目的:
- 様々ながんのEZH2阻害剤に対する耐性の基礎となるメカニズムを調査する.
- EZH2欠陥の固体腫瘍に対する新しい治療戦略を特定する.
主な方法:
- 異なるEZH2i感度を持つがん細胞系における全体的な翻訳後のヒストン変化のプロファイリング.
- MLL1,p300/CBP複合体とヒストンの改変 (H3K27me,H3K27ac) の相互作用の分析
- 固体腫瘍モデルにおけるEZH2,BRD4,MAPK阻害剤を含む組み合わせ治療の臨床前試験
主要な成果:
- MLL1- p300/ CBPの相互作用による腫瘍性転写再プログラミングは,H3K27meの損失とH3K27acの増加につながり,EZH2i応答を制限する.
- H3K27meとH3K27acの同時抑制は,転写抑制とMAPK経路依存を誘導する.
- EZH2およびBRD4阻害剤の併用,またはMAPK阻害によるトリプルセラピーは,EZH2変異の固体腫瘍の臨床前モデルにおいて有意な有効性と耐性を示した.
結論:
- MLL1発現レベルは,EZH2標的治療に対する反応を予測することができます.
- エピジェネティック・クロストラックとMAPK信号の同時抑制は,EZH2異常の固体腫瘍に対する有望な精密治療戦略を提供します.
- EZH2,BRD4,MAPK経路を標的とした組み合わせ治療は,EZH2阻害剤耐性を克服する有効なアプローチです.
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