Ancestry-dependent differences of PASK (Per-Arnt-Sim Kinase) inhibitor efficacy in triple-negative breast cancer under variable glucose conditions

Breast cancer mortality rates are nearly 40% higher in African American women than in women of European ancestry. A major contributor to this outcome is triple-negative breast cancer (TNBC), which disproportionately affects African American women and is associated with more aggressive disease. Per-Arnt-Sim Kinase (PASK) is a nutrient-sensitive protein kinase that regulates glucose and lipid metabolism. Previous studies have shown that PASK plays a significant role in breast cancer progression by promoting tumor growth through several metabolic and signaling pathways. Preliminary evidence suggests that the PASK inhibitor, BioE-1115, exhibits differential efficacy across TNBC cell lines of distinct ancestral backgrounds across varying glucose levels. TNBC cell lines representing African ancestry (HCC-1806 and MDA-MB-468) and European ancestry (MDA-MB-231) were cultured in media containing physiologically relevant glucose concentrations representing hypoglycemia (2.5 mM; 45 mg/dL), normoglycemia (5.5 mM; 100 mg/dL), hyperglycemia (11 mM; 198 mg/dL), and severe hyperglycemia (17.5 mM; 315.1 mg/dL). Cell viability assays were performed following BioE-1115 treatment to quantify ancestry- and glucose-dependent differences in the response to the inhibitor. Half-maximal inhibitory concentration (IC₅₀) values were calculated for each condition. BioE-1115 demonstrated distinct efficacy profiles across TNBC cell lines. The African-ancestry HCC-1806 and MDA-MB-468 cells displayed markedly reduced sensitivity to BioE-1115, with IC₅₀ values 1.3x-1.5x higher compared with the European-ancestry MDA-MB-231 cells under equivalent glucose conditions. Variability in inhibitor response was observed across glucose concentrations, indicating that metabolic state modifies PASK inhibitor efficacy. PASK inhibition preliminarily suggests ancestry-dependent differences in therapeutic response that are further modulated by glucose availability. These findings highlight the importance of integrating ancestry-informed genetic and metabolic context when evaluating targeted metabolic therapies for TNBC. This work provides foundational data supporting the need for precision-oncology approaches that consider both ancestry-linked biology and metabolic stressors.