Organoid screening reveals epigenetic vulnerabilities in human colorectal cancer

Kohta Toshimitsu, Ai Takano, Masayuki Fujii, Kazuhiro Togasaki, Mami Matano, Sirirat Takahashi, Takanori Kanai, Toshiro Sato

研究成果: Article査読

抄録

Precision oncology presumes an accurate prediction of drug response on the basis of the molecular profile of tumors. However, the extent to which patient-derived tumor organoids recapitulate the response of in vivo tumors to a given drug remains obscure. To gain insights into the pharmacobiology of human colorectal cancer (CRC), we here created a robust drug screening platform for patient-derived colorectal organoids. Application of suspension culture increased organoid scalability, and a refinement of the culture condition enabled incorporation of normal and precursor organoids to high-throughput drug screening. Drug screening identified bromodomain and extra-terminal (BET) bromodomain protein inhibitor as a cancer-selective growth suppressor that targets genes aberrantly activated in CRC. A multi-omics analysis identified an association between checkpoint with forkhead and ring finger domaines (CHFR) silencing and paclitaxel sensitivity, which was further validated by gene engineering of organoids and in xenografts. Our findings highlight the utility of multiparametric validation in enhancing the biological and clinical fidelity of a drug screening system. [Figure not available: see fulltext.]

本文言語English
ページ(範囲)605-614
ページ数10
ジャーナルNature Chemical Biology
18
6
DOI
出版ステータスPublished - 2022 6月

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学

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