类有机物
结直肠癌
药物重新定位
药品
转录组
曲美替尼
体内
药物发现
生物
药物开发
药理学
计算生物学
癌症
医学
癌症研究
生物信息学
内科学
生物技术
信号转导
基因
基因表达
生物化学
MAPK/ERK通路
遗传学
作者
Yunuo Mao,Wei Wang,Jingwei Yang,Xin Zhou,Yongqu Lu,Junpeng Gao,Xiao Wang,Lu Wen,Wei Fu,Fuchou Tang
出处
期刊:Protein & Cell
[Springer Nature]
日期:2023-06-22
卷期号:15 (4): 285-304
被引量:34
标识
DOI:10.1093/procel/pwad038
摘要
Abstract 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 signatures 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, trametinib, 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.
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