Targeting Cholesterol Metabolic Pathways to Enhance Efficacy of Standard Chemotherapy Drugs

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for approximately 25% of adult acute lymphoblastic leukemia cases, a population in which outcomes are substantially worse than in children. Despite high initial remission rates with cytotoxic chemotherapy, a substantial proportion of patients relapse, and no FDA-approved targeted therapies exist for T-ALL. Current treatment regimens are associated with severe long-term toxicities, underscoring the urgent need for strategies that improve chemotherapy efficacy while reducing the toxic burden on patients. Dysregulated cholesterol metabolism is a recognized feature of aggressive cancers, supporting rapid proliferation and survival. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1), encoded by SOAT1, catalyzes the esterification of free cholesterol for lipid droplet storage, a function upon which tumor cells develop heightened dependence due to unregulated cholesterol influx. We hypothesize that pharmacologic inhibition of ACAT1 with the selective inhibitor K604 would disrupt cholesterol homeostasis in T-ALL cells and sensitize them to standard chemotherapy. Consistent with this hypothesis, K604 enhanced doxorubicin-induced cell death across multiple T-ALL and breast cancer cell lines in a context-dependent manner, functioning primarily as a chemosensitizer rather than an independent cytotoxic agent. Mechanistically, concurrent K604 treatment increased intracellular doxorubicin accumulation in a time-dependent manner, consistent with progressive impairment of ABCB1-mediated efflux driven by membrane cholesterol remodeling. To situate these findings clinically, transcriptomic analysis of a publicly available adult T-ALL patient cohort was performed. SOAT1-high tumors exhibited a coherent multi-layered resistance state: suppression of the intrinsic apoptotic pathway, transcriptional depletion of oxidative phosphorylation, and a positive trend toward ABCB1 co-expression that was specific to the cholesterol esterification arm of the lipid network. Key transcriptomic associations replicated in an independent cohort of 174 patients across a distinct expression platform. Together, these findings support a model in which ACAT1-mediated cholesterol esterification contributes to a multi-dimensional chemoresistance phenotype in T-ALL, and identify K604 as a pharmacologic strategy for enhancing doxorubicin efficacy in this disease.