Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
The Cancer Animal Models Shared Resource of Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
Mol Cancer Ther. 2021 Feb;20(2):274-283. doi: 10.1158/1535-7163.MCT-20-0567. Epub 2020 Dec 8.
Liver kinase B1 ()-inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, which is essential for pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors , and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor-derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.
LKB1 失活肿瘤易受嘧啶代谢破坏的影响，而来氟米特作为一种治疗候选药物出现，因为其活性代谢物 A77-1726 抑制二氢乳清酸脱氢酶，该酶对嘧啶生物合成至关重要。然而，目前尚不清楚来氟米特是否抑制 LKB1 失活肿瘤，以及其对免疫系统的抑制作用是否会促进肿瘤生长。在这里，我们对各种 LKB1 失活的小鼠异种移植瘤、患者来源的异种移植瘤和基因工程小鼠模型中的来氟米特治疗进行了全面分析。我们还生成了一种小鼠肿瘤衍生的癌细胞系 WRJ388，该细胞系在所有动物中皮下植入后一个月内即可转移到肺部。该模型用于评估来氟米特控制远处转移的能力。来氟米特治疗使 HeLa 异种移植瘤缩小，并减弱了 H460 异种移植瘤、患者来源的异种移植瘤和免疫功能正常的基因工程小鼠模型中的肺腺癌的生长。有趣的是，来氟米特通过至少三种不同的机制抑制肿瘤生长。它导致 HeLa 细胞凋亡，诱导 H460 细胞 G 期细胞周期停滞，并促进 WRJ388 细胞 S 期细胞周期停滞。最后，来氟米特治疗在我们的新型肺癌转移模型中预防了 78%的动物发生肺转移。总之，这些结果表明来氟米特利用不同的途径抑制 LKB1 失活肿瘤的生长，并且还可以预防远处部位的癌症转移。因此，来氟米特应作为 LKB1 失活肿瘤的治疗剂进行评估。
