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メラノーマは,RTKまたはN-RASアップレギュレーションによるB-RAF (V600E) 阻害に対する耐性を獲得する
Ramin Nazarian1, Hubing Shi, Qi Wang
1Division of Dermatology/Department of Medicine, UCLA's Jonsson Comprehensive Cancer Center, 52-121 CHS, Los Angeles, California 90095-1750, USA.
Nature
|November 26, 2010
まとめ
PLX4032のようなBRAF阻害剤に対するメラノマ薬剤耐性は,二次的なBRAF変異ではなく,PDGFRBアップレギュレーションまたはNRAS変異から生じる. これらの経路をターゲットにすることで,BRAF阻害剤耐性メラノーマに対する新しい治療戦略が提供されます.
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:
- 活性化されたBRAFキナーゼ変異は, ~60%のメラノーマを含む, ~7%のヒトがんを誘発する.
- BRAF阻害剤は有望ですが,薬剤耐性の獲得は重要な臨床的課題です.
- 抵抗のメカニズムには,二次的なBRAF変異,MAPK再活性化,および代替生存経路が含まれています.
研究 の 目的:
- BRAF (V600E) 陽性メラノーマにおけるBRAF阻害剤PLX4032に対する得られた耐性のメカニズムを調査する.
- メラノーマ細胞がBRAF抑制を回避できるようにする代替経路または変異を特定する.
- 薬剤耐性を克服するための潜在的な治療戦略を探求する.
主な方法:
- 人工的に派生したPLX4032耐性メラノーマ細胞系を使用した.
- PLX4032耐性腫瘍および患者由来培養における検証された発見.
- PDGFRβおよびNRASの変異,MAPK経路の活性化,および薬物感受性を評価した.
主要な成果:
- 獲得抵抗は,二次的なBRAF変異ではなく,相互排他的PDGFRβアップレギュレーションまたはNRAS変異によって引き起こされた.
- PDGFRβのアップレギュレーションは,有意なMAPK再活性化なしに,代替生存経路の活性化につながった.
- NRAS変異はMAPK経路の活性化を引き起こし,MEK阻害剤に対する感受性を予測しました.
- PDGFRβまたはNRASのノックダウンにより,耐性細胞の成長が低下し,過剰発現により耐性が生じる.
結論:
- メラノマはBRAF ((V600E) 標的をRTK媒介経路またはRAS媒介のMAPK再活性化経由で回避するので,BRAFの二次変異ではない.
- PDGFRβおよびNRASの変異は,BRAF阻害剤に対する獲得抵抗性の重要なメカニズムを表しています.
- 代替生存経路またはMEKをターゲットにすることは,耐性メラノーマに対する潜在的な治療戦略を提供します.
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