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過剰なRas活性によって引き起こされる白血病におけるMEK抑制に対する反応と抵抗

Jennifer O Lauchle¹, Doris Kim, Doan T Le

¹Department of Pediatrics, University of California, San Francisco, California 94143, USA.

|September 4, 2009

まとめ

MEK阻害剤は,Nf1欠乏性急性骨髄性白血病 (AML) に対して有望であるが,骨髄増殖性疾患 (MPD) に対して有望ではない. 耐性メカニズムは特定の遺伝子変異を含み,標的がん治療の洞察を提供します.

科学分野:

腫瘍学腫瘍学
分子生物学は分子生物学である.
がん遺伝学がん遺伝学

背景:

Raf/MEK/ERK経路は,Nf1不活性化を含む,Ras経路不調の癌の主要な標的である.
Nf1は,Ras信号伝達を否定的に調節するGTPase活性化タンパク質である神経線維素をコードします.
MEKのターゲティングは,Nf1欠乏がんに対する潜在的な治療戦略を提供します.

研究の目的:

Nf1欠乏性骨髄増殖性疾患 (MPD) と急性骨髄性白血病 (AML) でのMEK阻害剤の有効性を評価する.
これらのがんにおいて,MEK阻害剤に対するデノボおよび獲得抵抗性のメカニズムを特定する.
Nf1変異がんにおける薬剤耐性を克服するための戦略を探求する.

主な方法:

Nf1欠乏性MPDとAMLのマウスモデルにおけるMEK阻害剤効果の比較.
レトロウイルス挿入型ミュータゲネシスによるAMLにおける協力性突然変異の誘導.
レトロウイルス統合のクローン化により,耐性遺伝子を特定し,特定された経路の機能分析を行う.

主要な成果:

MEK阻害剤は,Nf1欠乏症のMPDにおいて無効であった.
MEK阻害剤は,Nf1欠乏AMLの有意な割合で客観的な回帰を誘導しました.
薬剤耐性は,以前に存在していたAMLクローンから発生し,Rasgrp1,Rasgrp4,Mapk14 (p38alpha) を含む耐性遺伝子が特定されました.
RasGRP1濃度の上昇とp38キナーゼの活性低下は,耐性に関与していた.

結論:

MEK阻害剤は,Nf1欠乏性血液性悪性腫瘍において差異的な有効性を示しています.
RasGRP1やp38alphaを含むような抵抗メカニズムを理解することは,効果的な治療戦略の開発に不可欠です.
この研究は,標的治療への反応と原発がん細胞の抵抗に影響を与える遺伝子と経路を特定するための枠組みを提供します.

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