Sci Rep. 2025 Aug 6;15(1):28709. doi: 10.1038/s41598-025-14639-z.ABSTRACTHER2 overexpression/amplification (HER2+) occurs in approximately 15-20% of breast cancer (BC) and identifies a highly aggressive BC subtype. The cure rate of HER2 + BC has been significantly increased through recent clinical achievements; however, a non-negligible proportion of patients still either fails to respond or acquires resistance to targeted therapies, highlighting the need for novel treatment strategies. As demonstrated in robust preclinical studies, HER2 + BC is considered a neoplastic disease with a peculiar lipogenic phenotype, due to its crucial addiction to an exacerbated need for fatty acids (FAs) produced via FA synthase (FASN), the central lipogenic enzyme required for intracellular de novo FA biosynthesis. FASN is overexpressed/activated in most HER2 + BC cells sustaining their growth, proliferation, and aggressiveness through a reciprocal direct interplay with the HER2-driven oncogenic signaling. Recent evidence shows that rewiring of lipid metabolism in the presence of pharmacological HER2 inhibition impairs FASN up-regulation and activates the compensatory lipid metabolic pathway of FA uptake via the altered expression/activity of the transmembrane CD36 FA transporter. Thus, the latter is emerging as a potentially new and targettable mechanism of resistance to anti-HER2 therapies. Due to the limited availability of drug-like compounds that selectively target CD36, in this study we screened a library of commercial compounds through in silico docking on the crystal structure of the CD36 extracellular domain. We evaluated their chemical-physical, biological and metabolic properties through microscale thermophoresis and molecular dynamics analyses, cell viability assays performed in monotherapy and dual blockade, and gas chromatography-flame ionization detector and BODIPY C16 uptake analyses. Among the best ranked compounds, we selected two promising hits with micromolar affinity for CD36, showing in vitro that they decrease per se the proliferation of HER2 + BC cells resistant to anti-HER2 agents, induce apoptotic effects, significantly reduce FA intracellular internalization, and potentiate the cytotoxic activity of lapatinib, i.e. the most suitable anti-HER2 drug used in in vitro bioassays. Taken together, these findings support that our novel anti-CD36 small molecules should undergo hit-to-lead optimization to prospectively improve the efficacy of anti-HER2 agents in HER2 + BC refractory to targeted therapy.PMID:40770043 | DOI:10.1038/s41598-025-14639-z