首页|Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids

Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids

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Colorectal cancer(CRC)is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed.Here,we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors.To efficiently identify repurposed drugs for CRC,we developed a robust organoid-based drug screening system.By combining the repurposed drug library and computation-based drug prediction,335 drugs were tested and 34 drugs with anti-CRC effects were identified.More importantly,we conducted a detailed transcriptome analysis of drug responses and divided the drug response signa-tures into five representative patterns:differentiation induction,growth inhibition,metabolism inhibition,immune response promotion,and cell cycle inhibition.The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft(PDOX)system in vivo.We found that fedratinib,tra-metinib,and bortezomib exhibited effective anticancer effects.Furthermore,the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated.Our study offers an innovative approach for drug discovery,and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

colorectal cancerorganoidsdrug repurposingpatient-derived organoids-based xenograftmechanism of action

Yunuo Mao、Wei Wang、Jingwei Yang、Xin Zhou、Yongqu Lu、Junpeng Gao、Xiao Wang、Lu Wen、Wei Fu、Fuchou Tang

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School of Life Sciences,Biomedical Pioneering Innovation Center,Department of General Surgery,Third Hospital,Peking University,Beijing 100871,China

Beijing Advanced Innovation Center for Genomics(ICG),Ministry of Education Key Laboratory of Cell Proliferation and Differentiation,Beijing 100871,China

The Research Center of Stem Cell and Regenerative Medicine,School of Basic Medical Sciences,Cheeloo College of Medicine,Shandong University,Jinan 250012,China

Peking University Third Hospital Cancer Center,Beijing 100871,China

Peking-Tsinghua Center for Life Sciences,Peking University,Beijing 100871,China

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Beijing Advanced Innovation Center for Genomics国家自然科学基金

91959110

2024

10.1093/procel/pwad038

蛋白质与细胞

蛋白质与细胞

CSTPCD
影响因子：0.645
ISSN：
年,卷(期)：2024.15(4)
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