結腸直腸がんにおける標的型EGFR阻害に対する獲得抵抗性の分子進化

Luis A Diaz¹, Richard T Williams, Jian Wu

¹Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, Maryland 21287, USA. ldiaz1@jhmi.edu

Nature

|June 23, 2012

まとめ

珍しいKRAS変異は,結腸直腸腫瘍に先行して存在し,EGFR阻害療法中に現れる. 血液中のこれらのKRAS変異の検出は,抗EGFR抗体に対する獲得抵抗性を予測します.

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:

EGFRブロックに最初敏感であった結腸直腸腫瘍は,しばしば抵抗性を発症する.
抗EGFR抗体に対する得られた耐性のメカニズムは十分に理解されていません.
小分子阻害剤とは異なり,抗体ベースのEGFRブロックに対する耐性には明確な遺伝的標的がない.

研究の目的:

既にあるKRAS変異がEGFRの阻害に対する耐性を引き起こすという仮説を検証する.
抗EGFR抗体で治療された患者の循環中に突然変異したKRASDNAが検出できるかどうかを判断する.
耐性を予測するためのKRAS変異の非侵襲的検出の臨床的有用性を調査する.

主な方法:

パニチューマブを投与された患者におけるKRAS変異の循環腫瘍DNA (ctDNA) の分析.
分子技術を用いた血清におけるKRAS変異の検出.
変異のタイミングとクローン拡大を評価するための数学的モデリング.

主要な成果:

KRASワイルド型腫瘍を発症した患者の38%の血清に突然変異したKRASDNAが検出されました.
いくつかの患者では,複数の異なるKRAS変異が特定されました.
変異の出現は,通常,治療の5~6ヶ月間で発生し,事前に存在していたサブクローンを示唆しています.

結論:

KRAS変異の出現は,結腸直腸がんにおけるEGFRブロックに対する獲得抵抗の重要な媒介である.
血清におけるKRAS変異の非侵襲的検出は実現可能であり,耐性を予測することができます.
これらの発見は,標的治療に対する耐性の再現可能な発達を説明する.

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