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{'KRAS遺伝子変異は非小細胞肺癌を含むヒトの癌で頻度の高いがん遺伝子変異の一つである.発見から30年以上のKRAS変異陽性癌の治療法開発にもかかわらず,臨床的有用性を示す薬物は得られず,創薬不能な標的とされてきた.理由として,KRASとGTPの親和性は高く結合阻害は困難,KRASの下流シグナルや膜結合に必要な翻訳後修飾はいくつも平行しており,単一の経路や修飾反応の阻害では他の活性化が起こる,KRAS変異陽性癌は必ずしもKRASに生死が依存していないことなどが考えられる.2013年にGDP結合KRASに低分子化合物がはまるポケットが見出され,G12C変異KRASに限定的ながら,KRASを不活性なGDP結合型に非可逆的に固定する化合物が報告された.この発見に基づき,ソトラシブやアダグラシブなどのG12C特異的阻害剤が開発され,前者は2021年に米国で,2次治療以降のKRASG12C変異陽性非小細胞肺癌に対し迅速承認された.今後,G12C以外の直接阻害剤,G12C阻害剤との併用療法,耐性獲得後の対策,有効な患者選択のためのバイオマーカーなどについて,さらなる研究開発が待たれる.': [0]}, 'cited_by_api_url': 'https://api.openalex.org/works?filter=cites:W4283712951', 'counts_by_year': [], 'updated_date': '2024-09-19T00:37:53.535655', 'created_date': '2022-06-30'}