慢性リンパ球白血病におけるATR経路を標的とした合成致死性

Marwan Kwok¹, Nicholas Davies¹, Angelo Agathanggelou¹

¹School of Cancer Sciences, University of Birmingham, Birmingham, UK.

|August 28, 2015

まとめ

新しいATR阻害剤であるAZD6738は,DNA損傷応答 (DDR) 欠陥,特にTP53またはATM不活性化を有する慢性リンパ球性白血病 (CLL) 細胞を効果的に標的にします. このアプローチは,治療抵抗を克服し,これらの患者の病気の再発を防ぐための新しい戦略を提供します.

科学分野:

腫瘍学
分子生物学
遺伝学

背景:

TP53とATMの異常を含むDNA損傷応答 (DDR) の欠陥は,慢性リンパ球性白血病 (CLL) のゲノム不安定性と化学抵抗を誘発する.
現在の治療法では,DDRの欠陥を有するCLL患者における長期的な疾患制御に有効性が欠けている.
ATR経路の阻害は,これらの特定のCLL細胞を標的とした合成致死性戦略として調査されています.

研究の目的:

新型ATR阻害剤であるAZD6738の有効性を,TP53またはATMの欠陥を有するCLL細胞に対する標的治療として調査する.
DDR欠陥CLL細胞におけるATR阻害による合成致死性のメカニズムを解明する.

主な方法:

DDRタンパク質に対するAZD6738の効果は,ウェスタン・ブロッティングと免疫光で評価された.
細胞毒性は,光測定とプロピジアムヨウ素排除を用いて評価された.
TP53またはATM不活性化によるCLL細胞をマウスに移植し,AZD6738治療後に腫瘍負荷/サブクローン組成を分析した.

主要な成果:

AZD6738はATRシグナル伝達を強力に阻害し,p53またはATM欠陥のCLL細胞でDNA損傷とミトスの破滅を引き起こした.
この薬は,DDR欠陥CLL細胞に対する選択的細胞毒性と,化学療法との相乗効果を示した.
in vivo試験では,AZD6738治療後にATMまたはTP53の変化による腫瘍負荷の低下とCLLサブクローンの選択的減少が確認されました.

結論:

AZD6738のメカニズムとin vitro/ in vivoの有効性は,p53- nullまたはATM- nullのCLL細胞を標的としたことが実証されました.
この新しい治療法は,クローン進化を防ぐ可能性があり,これはCLLにおける治療抵抗性および再発の主要な要因です.

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