Abstract Breast cancer (BC) remains one of the leading causes of cancer-related death in women worldwide. HER2-positive BC accounts for approximately 15–20% of all cases and is associated with aggressive disease and poor prognosis. Although Lapatinib, a dual tyrosine kinase inhibitor (TKI), is a cornerstone in HER2+ BC therapy, the emergence of chemoresistance severely limits its long-term efficacy, a phenomenon that dyslipidemias may influence. We characterized a Lapatinib-resistant cell model (BT474LapRV2) to explore the impact of low-density lipoproteins (LDL) on chemoresistance mechanisms in HER2+ BC. LDL uptake was evaluated by flow cytometry and confocal microscopy. Functional assays, qPCR, Western blotting, and molecular docking were employed to assess changes in proliferation, apoptosis, and the regulation of drug metabolism and efflux pathways. LDL treatment promoted cell proliferation and resistance to apoptosis in both parental (BT474Par) and resistant BT474LapRV2 cells. This effect was associated with differential modulation of cholesterol-regulating proteins (LDLR, SREBP2), drug-metabolizing enzymes (CYP3A4, SULT1A1), and drug efflux transporters (ABCB1, ABCC1). Notably, LDL selectively upregulated SULT1A1 in resistant cells, suggesting a metabolic shift toward sulfation-mediated inactivation of Lapatinib. Molecular docking confirmed strong binding affinity of Lapatinib and its metabolites to SULT1A1, ABCC1, and ABCB1, supporting their role in drug detoxification and exportation. In parallel, LDL induced reactivation of HER2 expression in resistant cells, enhancing survival signaling. Data demonstrated that LDL facilitates Lapatinib resistance in HER2+ BC by remodeling drug and lipid metabolic pathways, notably through SULT1A1 overexpression and HER2 reactivation. These findings highlight LDL as a metabolic driver of chemoresistance and support the therapeutic potential of targeting lipid metabolism and phase II drug enzymes in resistant HER2+ BC.
García‐González et al. (Wed,) studied this question.