Targeting Metabolic Vulnerabilities in Breast Cancer Brain Metastasis

Brain metastasis diagnosis in breast cancer patients is a severe and incurable condition, with overall survival measured in months. This underscores the urgent need to develop novel treatment strategies to target breast cancers brain metastasis (BCBM). Breast cancers that metastasize to the brain must adapt to a lack of lipid and fatty acid availability in the brain environment. Due to the dependency on fatty acids for growth and survival, these brain-metastatic tumors may shift to acetate as a primary carbon source for fatty acid synthesis. Here, we show that the enzyme acetyl-CoA synthetase 2 (ACSS2) that converts acetate into acetyl-CoA plays a critical role on breast cancer brain metastatic growth. We show that breast cancer cells selected for brain metastasis contain elevated levels of ACSS2 and increased phosphorylation of ACSS2 at Ser267 compared to parental breast cancer cells. Moreover, we show that ACSS2 is specifically required for metastatic breast cancer growth in the brain but not in the mammary fat pad in vivo. Mechanistically, we show that ACSS2 regulates breast cancer brain metastatic cell survival by suppressing ferroptosis in an E2F Transcription Factor 1 (E2F1) dependent manner. Importantly, we show our novel brain-permeable small molecule ACSS2 inhibitor reduce BCBM growth, enhances sensitivity to radiation ex vivo and blocks BCBM growth in vivo. These results suggest a crucial role for ACSS2 signaling in regulating protection from ferroptosis in BCBM cells and identify a novel ACSS2 inhibitor as an agent for treating breast cancer brain metastasis. We also explore the relationship between mitochondrial fatty acid oxidation (FAO) key enzyme, acyl-CoA acetyltransferase 2 (ACAA2) and BCBM growth and survival. FAO and ACAA2 are elevated in BCBM cells and are required for BCBM mitochondrial respiration and BCBM growth and survival in vitro and in vivo. Taken together, these data suggest these metabolic adaptations in BCBM cells can serve as novel therapeutic targets.