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

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

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Protein Cell ›› 2024, Vol. 15 ›› Issue (4) : 285-304. DOI: 10.1093/procel/pwad038
RESEARCH ARTICLE

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

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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.

Keywords

colorectal cancer / organoids / drug repurposing / patient-derived organoids-based xenograft / mechanism of action

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Yunuo Mao, Wei Wang, Jingwei Yang, Xin Zhou, Yongqu Lu, Junpeng Gao, Xiao Wang, Lu Wen, Wei Fu, Fuchou Tang. Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids. Protein Cell, 2024, 15(4): 285‒304 https://doi.org/10.1093/procel/pwad038

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2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.
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