Abstract 7444: Hepatotoxicity from L-asparaginase is associated with lipid changes in a mouse model

Abstract L-asparaginase (Calaspargase-pegol, PEG) is currently an important component of acute lymphoblastic leukemia (ALL) treatment in children, adolescents, and young adults. Despite its high efficacy, toxicities including hepatotoxicity limit its use. Asparaginase-associated hepatotoxicity is often associated with obesity and fatty liver, highlighting lipid metabolism as a potential contributor to fatty liver. Therefore, we performed lipidomic analyses of plasma and liver from control and obese mice treated with one dose of PEG, to determine whether specific lipid moieties or classes may be associated with the hepatotoxicity produced by PEG. Control and obese 18-week-old male C57Bl6/J mice were treated with one dose of 3000 IU/kg PEG or vehicle (n = 6 per group). Hepatotoxicity was assessed one week later by liver histopathology and plasma alanine transaminase (ALT) and albumin levels. Liver and plasma lipidomic profiles were also analyzed by UHPLC-QTRAP-MS/MS. One week post Veh vs. PEG were compared using two-sided, unpaired t-tests. PEG increased liver steatosis scores in both control (Veh: 0.5±0.2, PEG: 3.7±0.3, p<0.001) and obese mice (Veh: 4.0±0.6, PEG: 6.7±0.2, p<0.01). While ALT levels did not show a clear pattern with PEG treatment, albumin level decreased in both control (Veh: 3.6±0.1, PEG: 2.7±0.2, p<0.01) and obese mice (Veh: 4.1±0.2, PEG: 2.8±0.1, p<0.01). Lipidomics analysis showed that plasma lipids generally decreased with PEG treatment in control (not shown) and more significantly in obese mice (Phosphatidylcholines [PC]: Veh 3000.0±381.1, PEG 507.2±71.5, p<0.001; Phosphatidylethanolamine [PE]: Veh 604.7±128.1, PEG 295.3±75.0, p<0.001; triglycerides [TG]: Veh 649.7±89.7, PEG 150.6±49.3, p<0.001). Similar patterns were observed in control (not shown) and obese livers for PC (Veh 11.1±0.8, PEG 5.7±0.8, p<0.001) and PE (Veh 6.7±0.8, PEG 3.5±0.5, p<0.001), whereas liver TG increased with treatment (Veh 220.1±113.5, PEG 586.6±113.4, p<0.001). Interestingly, there were strong negative correlations between steatosis score and liver PC (r2=0.46, p<0.001) and PE (r2=0.62, p<0.001). As low PC has been shown to induce fatty liver, this finding implies that PEG might induce steatosis via reduction in PC and its precursor, PE. Future work will investigate the mechanisms by which PEG reduces liver PE and PC levels, and whether this is causally related to steatosis and hepatotoxicity. Citation Format: Veronica Ruiz-Torres, Jennifer J. Chia, Michael Cohen, Jia Tan, Praveen Bandaru, Austin Brown, Van Huynh, Etan Orgel, Steven D. Mittelman. Hepatotoxicity from L-asparaginase is associated with lipid changes in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7444.