Abstract 2943: Severe hepatotoxicity of mithramycin therapy caused by altering expression of hepatocellular bile transporters

Abstract

Abstract Mithramycin has shown significant preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with inter-individual variation in genes involved in bile disposition: ABCB4(MDR3) rs2302387 and ABCB11(BSEP) rs4668115 variants reduce transporter expression (P<0.05) and were associated with ≥Grade 3 liver function test (LFT) elevations developing 24 hours after the third infusion of mithramycin (25mcg/kg, 6hr/infusion, qdx7, every 28 days;P<0.0040). A similar relationship was observed in a pediatric cohort genotyped for ABCB11. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, NTCP, OSTα/β) in several cell lines (Huh7, HepaRG, HepaRG BSEP (-/-)) and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P<0.0001), and mithramycin inhibited CDCA- and GW4046-induced FXR-GAL4 luciferase reporter activity (P<0.001). Mithramycin promoted GCDC-induced cytotoxicity in cells lacking the BSEP transporter and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P<0.01). Mithramycin is an FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low BSEP function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. Citation Format: Tristan M. Sissung, Phoebe A. Huang, Ralph Hauke, Edel McCrea, Cody J. Peer, Roberto H. Barbier, Jonathan D. Strope, Ariel M. Ley, Mary Zhang, Julie A. Hong, David Venzon, Jonathan P. Jackson, Kenneth R. Brouwer, Patrick Grohar, John Glod, Brigitte C. Widemann, Theo Heller, David S. Schrump, William D. Figg. Severe hepatotoxicity of mithramycin therapy caused by altering expression of hepatocellular bile transporters [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 2943.