Kryeziu Kushtrim, Moosavi Seyed H, Bergsland Christian H, Guren Marianne G, Eide Peter W, Totland Max Z, Lassen Kristoffer, Abildgaard Andreas, Nesbakken Arild, Sveen Anita, Lothe Ragnhild A
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Nydalen, P. O. Box 4953, 0424, Oslo, Norway.
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
J Transl Med. 2021 Sep 8;19(1):384. doi: 10.1186/s12967-021-03062-3.
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.
肿瘤异质性是治疗失败的主要原因。然而，癌症中药物敏感性随时间的变化尚未得到很好的描绘。患者来源的类器官（PDO）可能在体外预测临床药物反应，并提供以个性化方式评估新治疗策略的机会。在此，我们评估了一名微卫星稳定且KRAS突变的转移性直肠癌患者在肝再次切除和新辅助联合化疗后建立的五个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符，与转移性结直肠癌的PDO参考数据集相比，体外药物敏感性通常反映了临床反应和选择压力。来自初始与两个复发性转移环境的PDO显示出异质的细胞形态、蛋白质标志物表达和药物敏感性。对33种研究性抗癌药物的药物筛选文库进行的探索性分析表明，与初始转移的PDO相比，复发性疾病的PDO对SMAC模拟物LCL161的体外敏感性最强。功能分析证实了来自复发性转移的LCL161敏感PDO中的靶标抑制和凋亡诱导。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被确定为肝切除和标准全身治疗后复发的转移性直肠癌的一种可能的实验性治疗方法。
