Chemoresistance in the aggressive triple negative breast cancer, is associated with metabolic and morphologic changes, found in clinical samples and revealing a new vulnerability in increased numbers of lipid droplets.

The major obstacle in successfully treating triple negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous pre-clinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphological phenotype, which consists of polyploid giant cancer cells (PGCCs) giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy.