Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

中文翻译：

---

阻断脂质合成会诱导前列腺癌中的 DNA 损伤，并增加 PARP 抑制引起的细胞死亡

雄激素剥夺疗法（ADT）是前列腺癌的主要治疗方法；然而，ADT 总会产生耐药性，导致去势抵抗性前列腺癌 (CRPC)。前列腺癌进展的特点是由于脂肪酸合酶 (FASN) 的过度表达而导致脂肪酸从头合成增加，使该酶成为前列腺癌的治疗靶点。抑制 FASN 会导致细胞内神经酰胺和鞘磷脂含量增加，从而通过形成 DNA 双链断裂和细胞死亡而导致 DNA 损伤。我们发现，将 FASNi 与聚 ADP 核糖聚合酶 (PARP) 抑制剂奥拉帕尼 (通过阻断 DNA 损伤修复来诱导细胞死亡) 相结合，会导致细胞生长的减少比单独使用任何一种药物更明显。用 PARP 和 FASNi 组合处理的人 CRPC 类器官更小，细胞增殖减少，细胞凋亡和坏死增加。总之，这些数据表明，靶向 FASN 通过损害 DNA 损伤修复来提高 PARP 抑制剂的治疗效果，这表明应探索针对 CRPC 的联合疗法。