標的治療に対する大腸がんの適応的変異性
Mariangela Russo1,2, Giovanni Crisafulli3,2, Alberto Sogari3,2
1Candiolo Cancer Institute, FPO-IRCCS, Candiolo (TO) 10060, Italy. alberto.bardelli@unito.it mariangela.russo@unito.it.
Science (New York, N.Y.)
|November 9, 2019
まとめ
大腸がん細胞は バクテリアのように 標的治療に耐えるために 変異率を増やすことができます DNA修復遺伝子の ダウンレギュレーションによって引き起こされる この適応的変異性は 腫瘍が治療を回避するのを助けます
科学分野:
- 腫瘍学
- 分子生物学
- 遺伝学
背景:
- 薬剤耐性は がん治療における大きな課題で 既存の耐性細胞に起因することが多い
- ストレス下での生物の変異率を増加させる適応的変異性は,細菌では知られているが,ヒトの癌では理解されていない.
研究 の 目的:
- 人間の結腸直腸がん (CRC) 細胞が標的治療を回避するために適応的変異性を利用するかどうかを調査する.
- 治療によるCRCの変異性に基づく分子メカニズムを理解する.
主な方法:
- CRC細胞における表皮成長因子受容体 (EGFR) / BRAF経路の抑制
- DNA修復遺伝子発現の分析 (不一致修復と同型再結合)
- 薬剤耐性細胞と患者からの異種移植におけるDNA損傷,変異率,およびマイクロサテライトの不安定性の評価
主要な成果:
- EGFR/ BRAFの阻害は,DNA修復遺伝子のダウンレギュレーションと,持続性のある細胞のエラー傾向のあるポリメラーゼのアップレギュレーションにつながった.
- 患者からの異種移植と腫瘍の標本では,治療中にMMRタンパク質濃度が低下した.
- 標的治療はDNA損傷を誘発し 細胞変異性を高め マイクロサテライトの不安定性を引き起こす
結論:
- ヒトの結腸直腸がん細胞は,単細胞生物と同様に,治療圧力を回避するためにその変異性を高めることができます.
- 適応的変異性は,がんにおける薬剤耐性の新しいメカニズムを表しており,さらなる調査が必要である.
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