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.

中文翻译：

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基于人结直肠癌类器官的药物再利用筛选及机制分析。

结直肠癌（CRC）是一种高度异质性的癌症，探索新的治疗方案是一个需要解决的紧迫问题。在这里，我们建立了人类结直肠癌肿瘤衍生的类器官，它很好地代表了原始肿瘤的形态和分子异质性。为了有效地识别结直肠癌的重新利用药物，我们开发了一个强大的基于类器官的药物筛选系统。通过结合重新利用的药物库和基于计算的药物预测，测试了 335 种药物，并鉴定了 34 种具有抗 CRC 作用的药物。更重要的是，我们对药物反应进行了详细的转录组分析，并将药物反应特征分为五种代表性模式：分化诱导、生长抑制、代谢抑制、免疫反应促进和细胞周期抑制。候选药物的抗癌活性在已建立的基于患者的类器官异种移植（PDOX）体内系统中得到进一步验证。我们发现fedratinib、trametinib 和bortezomib 表现出有效的抗癌作用。此外，还评估了体外类器官和体内成对 PDOX 之间药物反应特征的一致性和不一致。我们的研究为药物发现提供了一种创新方法，药物反应的代表性转录组特征为开发结直肠癌的新型临床治疗方法提供了宝贵的资源。评估了体外类器官和体内成对 PDOX 之间药物反应特征的一致性和不一致。我们的研究为药物发现提供了一种创新方法，药物反应的代表性转录组特征为开发结直肠癌的新型临床治疗方法提供了宝贵的资源。评估了体外类器官和体内成对 PDOX 之间药物反应特征的一致性和不一致。我们的研究为药物发现提供了一种创新方法，药物反应的代表性转录组特征为开发结直肠癌的新型临床治疗方法提供了宝贵的资源。