Tumor heterogeneity is a primary cause of treatment failure. However, changes in drug sensitivity over time are not well mapped in cancer. Patient-derived organoids (PDOs) may predict clinical drug responses ex vivo and offer an opportunity to evaluate novel treatment strategies in a personalized fashion. Here we have evaluated spatio-temporal functional and molecular dynamics of five PDO models established after hepatic re-resections and neoadjuvant combination chemotherapies in a patient with microsatellite stable and KRAS mutated metastatic rectal cancer. Histopathological differentiation phenotypes of the PDOs corresponded with the liver metastases, and ex vivo drug sensitivities generally reflected clinical responses and selection pressure, assessed in comparison to a reference data set of PDOs from metastatic colorectal cancers. PDOs from the initial versus the two recurrent metastatic settings showed heterogeneous cell morphologies, protein marker expression, and drug sensitivities. Exploratory analyses of a drug screen library of 33 investigational anticancer agents showed the strongest ex vivo sensitivity to the SMAC mimetic LCL161 in PDOs of recurrent disease compared to those of the initial metastasis. Functional analyses confirmed target inhibition and apoptosis induction in the LCL161 sensitive PDOs from the recurrent metastases. Gene expression analyses indicated an association between LCL161 sensitivity and tumor necrosis factor alpha signaling and RIPK1 gene expression. In conclusion, LCL161 was identified as a possible experimental therapy of a metastatic rectal cancer that relapsed after hepatic resection and standard systemic treatment.

中文翻译：

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对复发性 KRAS 突变直肠癌肝转移的纵向离体药物基因组学鉴定的 SMAC 模拟 LCL161 敏感性增加

肿瘤异质性是治疗失败的主要原因。然而，药物敏感性随时间的变化并没有很好地反映在癌症中。患者衍生的类器官 (PDO) 可以预测体外临床药物反应，并提供以个性化方式评估新治疗策略的机会。在这里，我们评估了微卫星稳定和 KRAS 突变的转移性直肠癌患者在肝脏再次切除和新辅助联合化疗后建立的五种 PDO 模型的时空功能和分子动力学。PDO 的组织病理学分化表型与肝转移相对应，离体药物敏感性通常反映临床反应和选择压力，与来自转移性结直肠癌的 PDO 参考数据集进行比较评估。来自初始与两个复发转移设置的 PDO 显示出异质细胞形态、蛋白质标记表达和药物敏感性。对 33 种研究性抗癌药物的药物筛选库的探索性分析表明，与初始转移的 PDO 相比，复发性疾病 PDO 中对 SMAC 模拟 LCL161 的体外敏感性最强。功能分析证实了来自复发转移的 LCL161 敏感 PDO 中的靶标抑制和细胞凋亡诱导。基因表达分析表明 LCL161 敏感性与肿瘤坏死因子 α 信号传导和 RIPK1 基因表达之间存在关联。总之，LCL161 被确定为转移性直肠癌的一种可能的实验疗法，该癌在肝切除和标准全身治疗后复发。