Leflunomide Suppresses the Growth of LKB1-Inactivated Tumors in the Immune-Competent Host and Attenuates Distant Cancer Metastasis

Mol Cancer Ther. 2021 Feb;20(2):274-283. doi: 10.1158/1535-7163.MCT-20-0567. Epub 2020 Dec 8.

Abstract

Liver kinase B1 (LKB1)-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 de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, 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 G1 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Immune Tolerance / immunology*
  • Leflunomide / pharmacology
  • Leflunomide / therapeutic use*
  • Neoplasm Metastasis
  • Neoplasms / drug therapy*
  • Neoplasms / pathology

Substances

  • Enzyme Inhibitors
  • Leflunomide