Abstract 4838: Leflunomide inhibits the growth of LKB1-inactivated tumors in both xenograft and immunocompetent genetically engineered mouse models

Abstract

Abstract Introduction: LKB1 is the third mostly frequently mutated gene in lung adenocarcinoma, and is mutually exclusive with EGFR mutations. Furthermore, a recent clinical trial indicated that lung cancers with LKB1 mutations are unlikely to respond to immune checkpoint therapy. Therefore, there is an urgent need for novel therapies for LKB1-inactivated lung cancer. We previously demonstrated that leflunomide preferentially induces apoptosis in LKB1-null lung cancer cell lines in vitro. Here, we evaluated the effect of leflunomide in both a xenograft model and immune-competent genetically engineered mouse model (GEMM). Methods: LKB1-null H460 xenograft mice were treated with leflunomide (35mg/kg/day) for 23 days through oral gavage and tumor volume was measured every the other day. KrasG12D/Lkb1-/-Luciferase GEMM mice were treated with leflunomide (30mg/kg/day) for 44 days and tumor burden was measured by bioluminescence imaging (BLI) score every week. At the end of experiments, tumors were dissected, weighed, and analyzed by immunohistochemistry. Results: Although leflunomide is an FDA-approved agent to treat rheumatoid arthritis, its immune suppression function did not facilitate but inhibited the growth of KrasG12DLkb1-/- lung adenocarcinoma. This suppression was also observed in H460 xenografts, and leflunomide treatment did not alter animal weight in either model. Furthermore, distant cancer metastasis was not observed in leflunomide-treated GEMM. In residual tumors from the treated group, cleaved caspase-3 was not detectable but there was a significant decrease in Ki67 staining. This is consistent with our in vitro findings that leflunomide primarily inhibits cell proliferation through the promotion of G1 cell cycle arrest. Conclusion: Our findings indicate that leflunomide may be a viable reagent for the treatment of LKB1-mutated lung adenocarcinoma. Citation Format: Rui Jin, Xiuju Liu, Wei Peng, Yijian Fan, Boxuan Liu, Shuanying Yang, Chun-gen Xing, Melissa Gilbert-Ross, Adam Marcus, Wei Zhou. Leflunomide inhibits the growth of LKB1-inactivated tumors in both xenograft and immunocompetent genetically engineered mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4838.