COTは,MAPキナーゼ経路の再活性化を通じてRAF抑制に対する抵抗を誘発する
Cory M Johannessen1, Jesse S Boehm, So Young Kim
1Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature
|November 26, 2010
まとめ
RAF阻害剤に対するメラノーマの耐性は,MAP3K8 (COT/Tpl2) をターゲットにすることで克服することができます. このキナーゼは,RAFと独立してMAPK経路を活性化し,BRAF変異性メラノーマ患者の新しい治療戦略を提供します.
科学分野:
- 腫瘍学 腫瘍学
- 分子生物学は分子生物学である.
- 遺伝学 遺伝学とは
背景:
- BRAF変異はメラノーマの50〜70%を誘発し,MAPK経路への依存性を生み出します.
- RAFおよびMEK阻害剤は臨床的に成功していますが,耐性によって制限されています.
- 耐性メカニズムを特定することは,持続的な治療戦略の開発に不可欠です.
研究 の 目的:
- BRAF変異性メラノーマにおけるRAFキナーゼ阻害剤に対する耐性を誘発する新しい標的とメカニズムを特定する.
- 標的型メラノーマ治療に対する耐性を克服するための治療戦略を探求する.
主な方法:
- 抵抗メカニズムをスクリーニングするために,約600のキナーゼおよび関連するオープンリーディングフレーム (ORF) を表現しました.
- BRAF (V600E) メラノーマの細胞系と患者からのサンプルを使用した.
- MAPK経路の活性化と薬物耐性における特定された標的の役割を調査した.
主要な成果:
- MAP3K8 (COT/Tpl2) を,RAF抑制に対する耐性を授与する主要なMAPK経路アゴニストとして特定した.
- COTは,MEKに依存し,RAFに依存しないシグナリングを通じてERKを活性化します.
- COT発現は,メラノーマ細胞と患者の組織における新規および既得のレジスタンスと相関する.
結論:
- MAP3K8 (COT/Tpl2) は,BRAF変異性メラノーマにおけるRAF阻害剤に対する耐性の重要な媒介体である.
- COTキナーゼ活性をターゲットにしたり,組み合わせたMAPK経路を阻害したりすることは,潜在的な治療戦略です.
- 高通量機能スクリーンは,耐性メカニズムを効果的に特定し,新しい治療方法の情報を提供することができます.
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