Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

人表皮生长因子受体 2 阳性乳腺癌患者的脑转移瘤对控制全身性疾病的治疗难以治疗，而大脑微环境导致了这种治疗抵抗。不同组织的营养可用性可能有所不同，因此脑转移性乳腺癌生长所需的代谢适应可能会带来可用于治疗的不利因素。在这里，我们评估了大脑中的乳腺肿瘤与颅外部位的乳腺肿瘤之间的代谢差异，发现脑中生长的乳腺肿瘤的脂肪酸合成升高。我们确定这种表型是对大脑中相对于其他组织的脂质可用性降低的适应，导致在该部位生长的乳腺肿瘤对脂肪酸合成的位点特异性依赖性。脂肪酸合酶的遗传或药理学抑制可减少人表皮生长因子受体2阳性乳腺肿瘤在大脑中的生长，这表明转移部位营养可用性的差异可能导致可靶向的代谢依赖性。