Abstract 1712: CD36 enrichment in HER2+ mesenchymal stem cells potentiates therapy refractoriness in HER2+ breast cancer

Abstract Approximately 15-20% of breast cancers (BCs) are characterized by amplification/overexpression of HER2. Although the introduction of anti-HER2 drugs has improved the prognosis of HER2-positive (HER2+) BC patients, a considerable number of tumors fail to respond to or acquire resistance to targeted therapies, highlighting the need for new strategies. Emerging evidence shows that the reprogramming of fatty acid (FA) metabolism plays a key role in the aggressiveness and therapeutic resistance of HER2+ BC. HER2+ BC has been defined as a "lipogenic disease" due to the functional reciprocal crosstalk occurring between HER2-mediated oncogenic signaling and fatty acid (FA) biosynthesis via fatty acid synthase activity. Once lipid biosynthesis is inhibited by anti-HER2 agents, cancer cells could enhance their ability to uptake extracellular FAs to guarantee their supply. In this context, the functional role of the reprogramming of CD36-mediated FA uptake in HER2+ BC progression remains unclear. Our study provides an in-depth molecular, biological and functional characterization of the transmembrane FA transporter CD36 in epithelial (MET-like)- and mesenchymal (EMT-like) HER2+ breast cancer stem cell (CSC) subsets, selected HER2+ BC cell lines and patients treated with neoadjuvant trastuzumab. We reveal consistent enrichment of CD36 in HER2+ EMT-like CSCs from all tested preclinical and clinical therapy-refractory BC models. Notably, we demonstrate the functional interplay occurring between Wnt signaling regulation/activation and CD36 enrichment in HER2+ BC cells. Dual blockade of CD36 and HER2 increases the anti-CSC efficacy of anti-HER2 drugs. Additionally, expression of CD36 in intratumor HER2+ mesenchymal CSCs is significantly associated with resistance to trastuzumab in HER2+ BC patients. These results support the critical role of CD36-mediated FA uptake in HER2+ therapy-refractory BC. Our study provides evidence that targeting CD36 might be an effective therapeutic strategy for this malignancy. (Supported by AIRC) Citation Format: Lorenzo Castagnoli, Valeria Cancila, Martina Bigliardi, Matteo Dugo, Paola A. Corsetto, Claudia Chiodoni, Viola Regondi, Michela Francesconi, Antonino Belfiore, Andrea Vingiani, Giancarlo Pruneri, Francesca Ligorio, Elda Tagliabue, Claudio Tripodo, Claudio Vernieri, Tiziana Triulzi, Serenella M. Pupa. CD36 enrichment in HER2+ mesenchymal stem cells potentiates therapy refractoriness in HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1712.